Modulators of irf5 expression

ABSTRACT

The present embodiments provide methods, compounds, and compositions useful for inhibiting IRF5 expression, which may be useful for treating, preventing, or ameliorating a disease associated with IRF5.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No. 16/684,988, filed on Nov. 15, 2019, which claims the benefit of U.S. Provisional Patent Application No. 62/767,615, filed Nov. 15, 2018, the disclosure of which is incorporated herein by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SequenceListing22US3.txt created Oct. 28, 2021, which is 323 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

The present embodiments provide methods, compounds, and compositions useful for inhibiting Interferon Regulatory Factor 5 (IRF5; Humirf5) expression, and in certain instances, reducing the amount of IRF5 protein in a cell or animal, which can be useful for treating, preventing, or ameliorating a disease associated with IRF5.

BACKGROUND

Interferon Regulatory Factor 5 or IRF5 is an important regulator of inflammation and autoimmunity. There is a large body of evidence that links IRF5 risk alleles, which are associated with high expression, to the risk of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, inflammatory bowel disease, and multiple sclerosis (Hedl and Abhaham, J. Immunol., 2012, 188: 5348-5356; Kristjansdottir et al., J. Med. Genet. 2008, 45: 362-369; Graham et al., Nature Genet. 2006, 38: 550-555; Graham et al., PNAS, 2007, 104: 6758-6763).

The current standard of medical care for Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease in humans, involves treatment with anti-inflammatory agents, corticosteroids, immunomodulators, including azathioprine, or its active metabolite 6-mercaptopurine, methotrexate, biologic agents, including tumor necrosis factor antagonist therapies, anti-integrin therapies, and anti-interleukin (IL) 12/23 therapy. It is an object herein to provide compounds and compositions of high efficacy and tolerability for the treatment of diseases disclosed herein.

SUMMARY

Certain embodiments provided herein are compounds and methods for reducing the amount or activity of IRF5 mRNA, and in certain embodiments, reducing the amount of IRF5 protein in a cell or individual. In certain embodiments, the individual has a gastrointestinal disease. In certain embodiments, the individual has an inflammatory bowel disease. In certain embodiments, the disease is Crohn's disease. In certain embodiments, the disease is inflammatory bowel disease (IBD). In certain embodiments, the disease is ulcerative colitis. In certain embodiments, the disease is systemic lupus erythematosus (SLE). In certain embodiments, the disease is rheumatoid arthritis. In certain embodiments, the disease is primary biliary cirrhosis. In certain embodiments, the disease is systemic sclerosis. In certain embodiments, the disease is Sjogren's syndrome. In certain embodiments, the disease is multiple sclerosis. In certain embodiments, the disease is scleroderma. In certain embodiments, the disease is interstitial lung disease (SSc-ILD). In certain embodiments, the disease is polycystic kidney disease (PKD). In certain embodiments, the disease is chronic kidney disease (CKD). In certain embodiments, the disease is NASH. In certain embodiments, the disease is liver fibrosis. In certain embodiments, the disease is asthma. In certain embodiments, the disease is severe asthma. Certain compounds provided herein are directed to compounds and compositions that reduce inflammation in an animal.

Certain embodiments provided herein are directed to potent and tolerable compounds and compositions useful for inhibiting IRF5 expression, which can be useful for treating, preventing, ameliorating, or slowing progression of an inflammatory disease. Certain embodiments provided herein are directed to compounds and compositions that are more potent or have greater therapeutic value than compounds publicly disclosed.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank and NCBI reference sequence records are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

It is understood that the sequence set forth in each SEQ ID NO in the examples contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Compounds described by ION number indicate a combination of nucleobase sequence, chemical modification, and motif.

Definitions

Unless otherwise indicated, the following terms have the following meanings:

“2′-deoxyfuranosyl sugar moiety” or “2′-deoxyfuranosyl sugar” means a furanosyl sugar moiety having two hydrogens at the 2′-position. 2′-deoxyfuranosyl sugar moieties may be unmodified or modified and may be substituted at positions other than the 2′-position or unsubstituted. A β-D-2′-deoxyribosyl sugar moiety in the context of an oligonucleotide is an unsubstituted, unmodified 2′-deoxyfuranosyl and is found in naturally occurring deoxyribonucleic acids (DNA).

“2′-deoxynucleoside” means a nucleoside comprising 2′-H(H) furanosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

“2′-O-methoxyethyl” (also 2′-MOE) refers to a 2′-O(CH₂)₂—OCH₃) in the place of the 2′-OH group of a ribosyl ring. A 2′-O-methoxyethyl modified sugar is a modified sugar.

“2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means a nucleoside comprising a 2′-MOE modified sugar moiety.

“2′-substituted nucleoside” or “2-modified nucleoside” means a nucleoside comprising a 2′-substituted or 2′-modified sugar moiety. As used herein, “2′-substituted” or “2-modified” in reference to a sugar moiety means a sugar moiety comprising at least one 2′-substituent group other than H or OH.

“3′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 3′-most nucleotide of a particular compound.

“5′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 5′-most nucleotide of a particular compound.

“5-methylcytosine” means a cytosine with a methyl group attached to the 5 position.

“About” means within ±10% of a value. For example, if it is stated, “the compounds affected about 70% inhibition of PNPLA3”, it is implied that PNPLA3 levels are inhibited within a range of 60% and 80%.

“Administration” or “administering” refers to routes of introducing a compound or composition provided herein to an individual to perform its intended function. An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

“Administered concomitantly” or “co-administration” means administration of two or more compounds in any manner in which the pharmacological effects of both are manifest in the patient. Concomitant administration does not require that both compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive. Concomitant administration or co-administration encompasses administration in parallel or sequentially.

“Amelioration” refers to an improvement or lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain embodiments, amelioration includes a delay or slowing in the progression or severity of one or more indicators of a condition or disease. The progression or severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art.

“Animal” refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

“Antisense activity” means any detectable and/or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound to the target.

“Antisense compound” means a compound comprising an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, oligonucleotides, ribozymes, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

“Antisense inhibition” means reduction of target nucleic acid levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound.

“Antisense mechanisms” are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing.

“Antisense oligonucleotide” means an oligonucleotide having a nucleobase sequence that is complementary to a target nucleic acid or region or segment thereof. In certain embodiments, an antisense oligonucleotide is specifically hybridizable to a target nucleic acid or region or segment thereof.

“Bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety. “Bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

“Branching group” means a group of atoms having at least 3 positions that are capable of forming covalent linkages to at least 3 groups. In certain embodiments, a branching group provides a plurality of reactive sites for connecting tethered ligands to an oligonucleotide via a conjugate linker and/or a cleavable moiety.

“Cell-targeting moiety” means a conjugate group or portion of a conjugate group that is capable of binding to a particular cell type or particular cell types.

“cEt” or “constrained ethyl” means a ribosyl bicyclic sugar moiety wherein the second ring of the bicyclic sugar is formed via a bridge connecting the 4′-carbon and the 2′-carbon, wherein the bridge has the formula: 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration.

“cEt nucleoside” means a nucleoside comprising a cEt modified sugar moiety.

“Chemical modification” in a compound describes the substitutions or changes through chemical reaction, of any of the units in the compound relative to the original state of such unit. “Modified nucleoside” means a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase. “Modified oligonucleotide” means an oligonucleotide comprising at least one modified internucleoside linkage, a modified sugar, and/or a modified nucleobase.

“Chemically distinct region” refers to a region of a compound that is in some way chemically different than another region of the same compound. For example, a region having 2′-O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2′-O-methoxyethyl modifications.

“Chimeric antisense compounds” means antisense compounds that have at least 2 chemically distinct regions, each position having a plurality of subunits.

“Cleavable bond” means any chemical bond capable of being split. In certain embodiments, a cleavable bond is selected from among: an amide, a polyamide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, a di-sulfide, or a peptide.

“Cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

“Complementary” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Nucleobase matches or complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) and guanine (G) unless otherwise specified. Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches. By contrast, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

“Conjugate group” means a group of atoms that is attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

“Conjugate linker” means a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

“Conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

“Contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

“Designing” or “Designed to” refer to the process of designing a compound that specifically hybridizes with a selected nucleic acid molecule.

“Diluent” means an ingredient in a composition that lacks pharmacological activity, but is pharmaceutically necessary or desirable. For example, the diluent in an injected composition can be a liquid, e.g. saline solution.

“Differently modified” means chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified DNA nucleoside are “differently modified,” even though the DNA nucleoside is unmodified. Likewise, DNA and RNA are “differently modified,” even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified. For example, a nucleoside comprising a 2′-OMe modified sugar and an unmodified adenine nucleobase and a nucleoside comprising a 2′-OMe modified sugar and an unmodified thymine nucleobase are not differently modified.

“Dose” means a specified quantity of a compound or pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dose may require a volume not easily accommodated by a single injection. In such embodiments, two or more injections may be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reaction in an individual. In other embodiments, the compound or pharmaceutical agent is administered by infusion over an extended period of time or continuously. Doses may be stated as the amount of pharmaceutical agent per hour, day, week or month.

“Dosing regimen” is a combination of doses designed to achieve one or more desired effects.

“Double-stranded antisense compound” means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex, and wherein one of the two said oligomeric compounds comprises an oligonucleotide.

“Effective amount” means the amount of compound sufficient to effectuate a desired physiological outcome in an individual in need of the compound. The effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual's medical condition, and other relevant factors.

“Efficacy” means the ability to produce a desired effect.

“Expression” includes all the functions by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation.

“Gapmer” means an oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.”

“Hybridization” means the annealing of oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an oligonucleotide and a nucleic acid target.

“Immediately adjacent” means there are no intervening elements between the immediately adjacent elements of the same kind (e.g. no intervening nucleobases between the immediately adjacent nucleobases).

“Individual” means a human or non-human animal selected for treatment or therapy.

“Inhibiting the expression or activity” refers to a reduction or blockade of the expression or activity relative to the expression of activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.

“Internucleoside linkage” means a group or bond that forms a covalent linkage between adjacent nucleosides in an oligonucleotide. “Modified internucleoside linkage” means any internucleoside linkage other than a naturally occurring, phosphate internucleoside linkage. Non-phosphate linkages are referred to herein as modified internucleoside linkages.

“IRF5” means any nucleic acid or protein of IRF5. “IRF5 nucleic acid” means any nucleic acid encoding IRF5. For example, in certain embodiments, an IRF5 nucleic acid includes a DNA sequence encoding IRF5, an RNA sequence transcribed from DNA encoding IRF5 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding IRF5. “IRF5 mRNA” means an mRNA encoding a IRF5 protein. The target may be referred to in either upper or lower case.

“IRF5 specific inhibitor” refers to any agent capable of specifically inhibiting IRF5 RNA and/or IRF5 protein expression or activity at the molecular level. For example, IRF5 specific inhibitors include nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of IRF5 RNA and/or IRF5 protein.

“Lengthened oligonucleotides” are those that have one or more additional nucleosides relative to an oligonucleotide disclosed herein, e.g. a parent oligonucleotide.

“Linked nucleosides” means adjacent nucleosides linked together by an internucleoside linkage.

“Linker-nucleoside” means a nucleoside that links an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of a compound. Linker-nucleosides are not considered part of the oligonucleotide portion of a compound even if they are contiguous with the oligonucleotide.

“Mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned. For example, nucleobases including but not limited to a universal nucleobase, inosine, and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with respect to nucleobase to which it hybridized. As another example, a nucleobase of a first oligonucleotide that is not capable of hybridizing to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned is a mismatch or non-complementary nucleobase.

“Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating IRF5 RNA can mean to increase or decrease the level of IRF5 RNA and/or IRF5 protein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, an IRF5 compound can be a modulator that decreases the amount of IRF5 RNA and/or IRF5 protein in a cell, tissue, organ or organism.

“MOE” means methoxyethyl.

“Monomer” refers to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides.

“Motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

“Natural” or “naturally occurring” means found in nature.

“Non-bicyclic modified sugar” or “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

“Nucleic acid” refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

“Nucleobase” means a heterocyclic moiety capable of pairing with a base of another nucleic acid. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally occurring nucleobase that is chemically modified. A “universal base” or “universal nucleobase” is a nucleobase other than a naturally occurring nucleobase and modified nucleobase, and is capable of pairing with any nucleobase.

“Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.

“Nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

“Oligomeric compound” means a compound comprising a single oligonucleotide and, optionally, one or more additional features, such as a conjugate group or terminal group.

“Oligonucleotide” means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another. Unless otherwise indicated, oligonucleotides consist of 8-80 linked nucleosides. “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified. “Unmodified oligonucleotide” means an oligonucleotide that does not comprise any sugar, nucleobase, or internucleoside modification.

“Parent oligonucleotide” means an oligonucleotide whose sequence is used as the basis of design for more oligonucleotides of similar sequence but with different lengths, motifs, and/or chemistries. The newly designed oligonucleotides may have the same or overlapping sequence as the parent oligonucleotide.

“Parenteral administration” means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

“Pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an individual. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water-for-injection.

“Pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

“Pharmaceutical agent” means a compound that provides a therapeutic benefit when administered to an individual.

“Pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition may comprise one or more compounds or salt thereof and a sterile aqueous solution.

“Phosphorothioate linkage” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom. A phosphorothioate internucleoside linkage is a modified internucleoside linkage.

“Phosphorus moiety” means a group of atoms comprising a phosphorus atom. In certain embodiments, a phosphorus moiety comprises a mono-, di-, or tri-phosphate, or phosphorothioate.

“Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an oligomeric compound.

“Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time from minutes to indefinitely.

“Prodrug” means a compound in a form outside the body which, when administered to an individual, is metabolized to another form within the body or cells thereof. In certain embodiments, the metabolized form is the active, or more active, form of the compound (e.g., drug). Typically conversion of a prodrug within the body is facilitated by the action of an enzyme(s) (e.g., endogenous or viral enzyme) or chemical(s) present in cells or tissues, and/or by physiologic conditions.

“Reduce” means to bring down to a smaller extent, size, amount, or number.

“RefSeq No.” is a unique combination of letters and numbers assigned to a sequence to indicate the sequence is for a particular target transcript (e.g., target gene). Such sequence and information about the target gene (collectively, the gene record) can be found in a genetic sequence database. Genetic sequence databases include the NCBI Reference Sequence database, GenBank, the European Nucleotide Archive, and the DNA Data Bank of Japan (the latter three forming the International Nucleotide Sequence Database Collaboration or INSDC).

“Region” is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic.

“RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2, but not through RNase H, to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.

“Segments” are defined as smaller or sub-portions of regions within a nucleic acid.

“Side effects” means physiological disease and/or conditions attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality.

“Single-stranded” in reference to a compound means the compound has only one oligonucleotide.

“Self-complementary” means an oligonucleotide that at least partially hybridizes to itself. A compound consisting of one oligonucleotide, wherein the oligonucleotide of the compound is self-complementary, is a single-stranded compound. A single-stranded compound may be capable of binding to a complementary compound to form a duplex.

“Sites” are defined as unique nucleobase positions within a target nucleic acid.

“Specifically hybridizable” refers to an oligonucleotide having a sufficient degree of complementarity between the oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids. In certain embodiments, specific hybridization occurs under physiological conditions.

“Specifically inhibit” with reference to a target nucleic acid means to reduce or block expression of the target nucleic acid while exhibiting fewer, minimal, or no effects on non-target nucleic acids. Reduction does not necessarily indicate a total elimination of the target nucleic acid's expression.

“Standard cell assay” means assay(s) described in the Examples and reasonable variations thereof

“Standard in vivo experiment” means the procedure(s) described in the Example(s) and reasonable variations thereof.

“Stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

“Sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a β-D-ribosyl moiety, as found in naturally occurring RNA, or a β-D-2′-deoxyribosyl sugar moiety as found in naturally occurring DNA. As used herein, “modified sugar moiety” or “modified sugar” means a sugar surrogate or a furanosyl sugar moiety other than a β-D-ribosyl or a β-D-2′-deoxyribosyl. Modified furanosyl sugar moieties may be modified or substituted at a certain position(s) of the sugar moiety, substituted, or unsubstituted, and they may or may not have a stereoconfiguration other than β-D-ribosyl. Modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars.

“Sugar surrogate” means a modified sugar moiety that does not comprise a furanosyl or tetrahydrofuranyl ring (is not a “furanosyl sugar moiety”) and that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or nucleic acids.

“Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

“Target gene” refers to a gene encoding a target.

“Targeting” means the specific hybridization of a compound to a target nucleic acid in order to induce a desired effect.

“Target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” all mean a nucleic acid capable of being targeted by compounds described herein.

“Target region” means a portion of a target nucleic acid to which one or more compounds is targeted.

“Target segment” means the sequence of nucleotides of a target nucleic acid to which a compound is targeted. “5′ target site” refers to the 5′-most nucleotide of a target segment. “3′ target site” refers to the 3′-most nucleotide of a target segment.

“Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

“Therapeutically effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual.

“Treat” refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal.

Certain Embodiments

Certain embodiments provide methods, compounds and compositions for inhibiting Interferon Regulatory Factor 5 (IRF5) expression.

Certain embodiments provide compounds targeted to an IRF5 nucleic acid. In certain embodiments, the IRF5 nucleic acid has the sequence set forth in RefSeq or GENBANK Accession No. U51127.1 (incorporated by reference, disclosed herein as SEQ ID NO: 4); GENBANK Accession No. NT_007933.14 truncated from nucleotides 53761170 to U.S. Pat. No. 53,774,065 (incorporated by reference, disclosed herein as SEQ ID NO: 2); GENBANK Accession No. DC427600.1 (incorporated by reference, disclosed herein as SEQ ID NO: 5); GENBANK Accession No. NM_001098627.3 (incorporated by reference, disclosed herein as SEQ ID NO: 1); GENBANK Accession No. NM_001098629.2 (incorporated by reference, disclosed herein as SEQ ID NO: 3); GENBANK Accession No. NM_001098630.2 (incorporated by reference, disclosed herein as SEQ ID NO: 6); GENBANK Accession No. NM_001242452.2 (incorporated by reference, disclosed herein as SEQ ID NO: 7); GENBANK Accession No. NM_032643.4 (incorporated by reference, disclosed herein as SEQ ID NO: 8); and GENBANK Accession No. NC 000007.14 truncated from nucleotides 128935001 to 128953000 (incorporated by reference, disclosed herein as SEQ ID NO: 9). In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

In certain embodiments, the compound comprises a modified oligonucleotide 16 linked nucleosides in length. In certain embodiments, the compound is an antisense compound or oligomeric compound.

Certain embodiments provide a compound comprising a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide is 16 to 30 linked nucleosides in length.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

Certain embodiments provide a compound comprising a modified oligonucleotide 12 to 30 linked nucleosides in length and complementary within nucleobases 4366-4381, 5141-5156, 5140-5160, 5179-5194, 11544-11559, 11542-11596, 11736-11751, 11737-11752, 11720-11790, or 11794-11809 of SEQ ID NO: 2, wherein said modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 2. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide is 16 to 30 linked nucleosides in length.

In certain embodiments, compounds target nucleotides 11737-11752 of an IRF5 nucleic acid. In certain embodiments, compounds target within nucleotides 4366-4381, 5141-5156, 5140-5160, 5179-5194, 11544-11559, 11542-11596, 11736-11751, 11737-11752, 11720-11790, or 11794-11809 of an IRF5 nucleic acid having the nucleobase sequence of SEQ ID NO: 2. In certain embodiments, compounds have at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleotides 4366-4381, 5141-5156, 5140-5160, 5179-5194, 11544-11559, 11542-11596, 11736-11751, 11737-11752, 11720-11790, or 11794-11809 of an IRF5 nucleic acid having the nucleobase sequence of SEQ ID NO: 2. In certain embodiments, these compounds are antisense compounds, oligomeric compounds, or oligonucleotides.

In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion any one of SEQ ID NOs: 168, 228, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the modified oligonucleotide is 16 to 30 linked nucleosides in length.

In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the modified oligonucleotide is 16 to 30 linked nucleosides in length.

In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294.

In certain embodiments, compounds targeted to IRF5 are ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, and 786548. Out of over 1,320 compounds that were screened as described in the Examples section below, ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, and 786548 emerged as the top lead compounds. In particular, ION 729018 exhibited significant efficacy and tolerability out of over 1,320 compounds.

In certain embodiments, any of the foregoing modified oligonucleotides comprises at least one modified internucleoside linkage, at least one modified sugar, and/or at least one modified nucleobase.

In certain embodiments, any of the foregoing modified oligonucleotides comprises at least one modified sugar. In certain embodiments, at least one modified sugar comprises a 2′-O-methoxyethyl group. In certain embodiments, at least one modified sugar is a bicyclic sugar, such as a 4′-CH(CH3)-O-2′ group, a 4′-CH2-O-2′ group, or a 4′-(CH2)2-O-2′group.

In certain embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage, such as a phosphorothioate internucleoside linkage.

In certain embodiments, any of the foregoing modified oligonucleotides comprises at least one modified nucleobase, such as 5-methylcytosine.

In certain embodiments, any of the foregoing modified oligonucleotides comprises:

a gap segment consisting of linked deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide is 12 to 30 linked nucleosides in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the modified oligonucleotide is 16 to 30 linked nucleosides in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the modified oligonucleotide is 16 linked nucleosides in length having a nucleobase sequence consisting of the sequence recited in any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 228, 168, 1270, 1272, and 1294, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound consists of a modified oligonucleotide 16 linked nucleobases in length having a nucleobase sequence consists of the sequence recited in SEQ ID NO: 228, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 717, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each of the nucleosides in the 5′ wing segment comprises a cEt sugar (kk); wherein the nucleosides of the 3′ wing segment comprise from 5′ to 3′ direction of a cEt sugar, a 2′-MOE sugar, a cEt sugar, and a 2′-MOE sugar (keke); wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 717 and 1340, wherein the modified oligonucleotide comprises

a gap segment consisting of nine linked deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each of the nucleosides in the 5′ wing segment comprises a cEt sugar (kk); wherein the nucleosides of the 3′ wing segment from 5′ to 3′ direction comprise a 2′-MOE sugar, a 2′-MOE sugar, a 2′-MOE sugar, a cEt sugar and a cEt sugar (eeekk); wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of ION 729018 or salt thereof, having the following chemical structure:

In certain embodiments, a compound comprises or consists of the sodium salt of ION 729018, having the following chemical structure:

In any of the foregoing embodiments, the compound or oligonucleotide can be at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% complementary to a nucleic acid encoding IRF5.

In any of the foregoing embodiments, the compound can be single-stranded. In certain embodiments, the compound comprises deoxyribonucleotides. In certain embodiments, the compound is double-stranded. In certain embodiments, the compound is double-stranded and comprises ribonucleotides. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In any of the foregoing embodiments, the compound can be 8 to 80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked nucleosides in length. In certain embodiments, the compound comprises or consists of an oligonucleotide.

In certain embodiments, compounds or compositions provided herein comprise a pharmaceutically acceptable salt of the modified oligonucleotide. In certain embodiments, the salt is a sodium salt. In certain embodiments, the salt is a potassium salt.

In certain embodiments, the compounds or compositions as described herein are active by virtue of having at least one of an in vitro IC₅₀ of less than 2 μM, less than 1.5 μM, less than 1 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, less than 0.1 μM, less than 0.05 μM, less than 0.04 μM, less than 0.03 μM, less than 0.02 μM, or less than 0.01 μM.

In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having at least one of an increase in alanine transaminase (ALT) or aspartate transaminase (AST) value of no more than 4 fold, 3 fold, or 2 fold over control animals, or an increase in liver, spleen, or kidney weight of no more than 30%, 20%, 15%, 12%, 10%, 5%, or 2% compared to control animals. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase of ALT or AST over control animals. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase in liver, spleen, or kidney weight over control animals.

Certain embodiments provide a composition comprising the compound of any of the aforementioned embodiments or any pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. In certain embodiments, the composition has a viscosity less than about 40 centipoise (cP), less than about 30 centipoise (cP), less than about 20 centipoise (cP), less than about 15 centipoise (cP), or less than about 10 centipoise (cP). In certain embodiments, the composition having any of the aforementioned viscosities comprises a compound provided herein at a concentration of about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, or about 300 mg/mL. In certain embodiments, the composition having any of the aforementioned viscosities and/or compound concentrations has a temperature of room temperature, or about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C.

Certain Indications

Certain embodiments provided herein relate to methods of inhibiting IRF5 expression, which can be useful for treating, preventing, or ameliorating a disease associated with IRF5 in an individual, by administration of a compound that targets IRF5. In certain embodiments, the compound can be a IRF5 specific inhibitor. In certain embodiments, the compound can be an antisense compound, an oligomeric compound, or an oligonucleotide targeted to IRF5.

Examples of diseases associated with IRF5 treatable, preventable, and/or ameliorable with the methods provided herein include inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, and severe asthma. Certain compounds provided herein are directed to compounds and compositions that reduce inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in an individual. Certain compounds provided herein are directed to compounds and compositions that reduce inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual, comprising administering a compound targeted to IRF5 to the individual, thereby reducing or inhibiting reduces inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual.

In certain embodiments, a method of treating, preventing, or ameliorating a disease associated with IRF5 in an individual comprises administering to the individual a compound comprising a IRF5 specific inhibitor, thereby treating, preventing, or ameliorating the disease. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with IRF5. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an gastrointestinal disease. In certain embodiments, the gastrointestinal disease is ulcerative colitis or Crohn's disease. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound improves, preserves, or prevents inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in an animal.

In certain embodiments, a method of treating, preventing, or ameliorating inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in an animal comprises administering to the individual a compound comprising a IRF5 specific inhibitor, thereby treating, preventing, or ameliorating inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production. In certain embodiments, a method of treating, preventing, or ameliorating inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual, comprising administering a compound targeted to IRF5 to the individual, thereby reducing or inhibiting reduces inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound improves, preserves, or prevents inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production. In certain embodiments, administering the compound improves, preserves, or prevents inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with IRF5.

In certain embodiments, a method of inhibiting expression of IRF5 in an individual having, or at risk of having, a disease associated with IRF5 comprises administering to the individual a compound comprising a IRF5 specific inhibitor, thereby inhibiting expression of IRF5 in the individual. In certain embodiments, administering the compound inhibits expression of IRF5 in the gastrointestinal tract. In certain embodiments, administering the compound inhibits expression of IRF5 in the liver. In certain embodiments, administering the compound inhibits expression of IRF5 in the lungs. In certain embodiments, administering the compound inhibits expression of IRF5 in the kidneys. In certain embodiments, administering the compound inhibits expression of IRF5 in the joints. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is a gastrointestinal disease. In certain embodiments, the gastrointestinal disease is ulcerative colitis or Crohn's disease. In certain embodiments, the individual has, or is at risk of having, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. In certain embodiments, the individual has, or is at risk of having, inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production. In certain embodiments, the individual has, or is at risk of having, inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound improves, preserves, or prevents inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production. In certain embodiments, administering the compound improves, preserves, or prevents inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss.

In certain embodiments, a method of inhibiting expression of IRF5 in a cell comprises contacting the cell with a compound comprising a IRF5 specific inhibitor, thereby inhibiting expression of IRF5 in the cell. In certain embodiments, the cell is a gastrointestinal tract cell. In certain embodiments, the cell is a liver cell. In certain embodiments, the cell is a kidney cell. In certain embodiments, the cell is a lung cell. In certain embodiments, the cell is in the gastrointestinal tract, the lungs, the liver, the kidney, or any other organ. In certain embodiments, the cell is in the gastrointestinal tract of an individual who has, or is at risk of having, inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In certain embodiments, a method of reducing or inhibiting inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in an individual having, or at risk of having, a disease associated with IRF5 comprises administering to the individual a compound comprising a IRF5 specific inhibitor, thereby reducing or inhibiting inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in the individual. In certain embodiments, a method of reducing or inhibiting inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual having, or at risk of having, a disease associated with IRF5 comprises administering to the individual a compound comprising a IRF5 specific inhibitor, thereby reducing or inhibiting inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in the individual. In certain embodiments, the individual has, or is at risk of having, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with IRF5.

Certain embodiments are drawn to a compound comprising a IRF5 specific inhibitor for use in treating a disease associated with IRF5. In certain embodiments, the disease is inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally.

Certain embodiments are drawn to a compound comprising an IRF5 specific inhibitor for use in reducing or inhibiting inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in an individual having, or at risk of having, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. In certain embodiments, the IRF5 specific inhibitor for use reduces or inhibits inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to the use of a compound comprising a IRF5 specific inhibitor for the manufacture or preparation of a medicament for treating a disease associated with IRF5. Certain embodiments are drawn to the use of a compound comprising a IRF5 specific inhibitor for the preparation of a medicament for treating a disease associated with IRF5. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is a gastrointestinal disease. In certain embodiments, the gastrointestinal disease is ulcerative colitis or Crohn's disease. In certain embodiments, the disease is inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to the use of a compound comprising a IRF5 specific inhibitor for the manufacture or preparation of a medicament for reducing or inhibiting inflammation, cirrhosis, fibrosis, proteinuria, joint inflammation, autoantibody production, inflammatory cell infiltration, collagen deposits, or inflammatory cytokine production in an individual having, or at risk of having, a disease associated with IRF5. In certain embodiments, the IRF5 specific inhibitor for the manufacture or preparation of the medicament reduces or inhibits inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual. In certain embodiments, the disease is inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. Certain embodiments are drawn to use of a compound comprising a IRF5 specific inhibitor for the preparation of a medicament for treating a disease associated with IRF5. In certain embodiments, the disease is inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, primary biliary cirrhosis, systemic sclerosis, Sjogren's syndrome, multiple sclerosis, scleroderma, interstitial lung disease (SSc-ILD), polycystic kidney disease (PKD), chronic kidney disease (CKD), NASH, liver fibrosis, asthma, or severe asthma. In certain embodiments, the compound comprises an antisense compound targeted to IRF5. In certain embodiments, the compound comprises an oligonucleotide targeted to IRF5. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, a compound comprises a modified oligonucleotide 16 to 30 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 228, 168, 717, 1340, 1270, 1272, and 1294. In certain embodiments, the compound is ION 729018, 728958, 785525, 785674, 785675, 786503, 786524, or 786548. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In any of the foregoing methods or uses, the compound can be targeted to IRF5. In certain embodiments, the compound comprises or consists of a modified oligonucleotide, for example, a modified oligonucleotide 8 to 80 linked nucleosides in length, 10 to 30 linked nucleosides in length, 12 to 30 linked nucleosides in length, or 20 linked nucleosides in length. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NOs: 37-1356. In certain embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar and/or at least one modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage, the modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl modified sugar, and the modified nucleobase is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide comprises a gap segment consisting of linked deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; and a 3′ wing segment consisting of linked nucleosides, wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

In any of the foregoing embodiments, the modified oligonucleotide is 12 to 30, 15 to 30, 15 to 25, 15 to 24, 16 to 24, 17 to 24, 18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to 22, 16 to 20, or 16 or 20 linked nucleosides in length. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NOs: 37-1356.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 228, 168, 1270, 1272, and 1294, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound consists of a modified oligonucleotide 16 linked nucleobases in length having a nucleobase sequence consists of the sequence recited in SEQ ID NO: 228, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 717, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each of the nucleosides in the 5′ wing segment comprises a cEt sugar (kk); wherein the nucleosides of the 3′ wing segment comprise from 5′ to 3′ direction of a cEt sugar, a 2′-MOE sugar, a cEt sugar, and a 2′-MOE sugar (keke); wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 717 and 1340, wherein the modified oligonucleotide comprises

a gap segment consisting of nine linked deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each of the nucleosides in the 5′ wing segment comprises a cEt sugar (kk); wherein the nucleosides of the 3′ wing segment from 5′ to 3′ direction comprise a 2′-MOE sugar, a 2′-MOE sugar, a 2′-MOE sugar, a cEt sugar and a cEt sugar (eeekk); wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of ION 729018 or salt thereof, having the following chemical structure:

In certain embodiments, a compound comprises or consists of the sodium salt of ION 729018, having the following chemical structure:

In any of the foregoing methods or uses, the compound can be administered parenterally. For example, in certain embodiments the compound can be administered through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

Certain Compounds

In certain embodiments, compounds described herein can be antisense compounds. In certain embodiments, the antisense compound comprises or consists of an oligomeric compound. In certain embodiments, the oligomeric compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

In certain embodiments, a compound described herein comprises or consists of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

In certain embodiments, a compound or antisense compound is single-stranded. Such a single-stranded compound or antisense compound comprises or consists of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises or consists of an oligonucleotide and optionally a conjugate group. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide is modified. In certain embodiments, the oligonucleotide of a single-stranded antisense compound or oligomeric compound comprises a self-complementary nucleobase sequence.

In certain embodiments, compounds are double-stranded. Such double-stranded compounds comprise a first modified oligonucleotide having a region complementary to a target nucleic acid and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the modified oligonucleotide is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase. In certain embodiments, compound comprises a conjugate group. In certain embodiments, one of the modified oligonucleotides is conjugated. In certain embodiments, both the modified oligonucleotides are conjugated. In certain embodiments, the first modified oligonucleotide is conjugated. In certain embodiments, the second modified oligonucleotide is conjugated. In certain embodiments, the first modified oligonucleotide is 16-30 linked nucleosides in length and the second modified oligonucleotide is 16-30 linked nucleosides in length. In certain embodiments, one of the modified oligonucleotides has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of SEQ ID NOs: 37-1356.

In certain embodiments, antisense compounds are double-stranded. Such double-stranded antisense compounds comprise a first oligomeric compound having a region complementary to a target nucleic acid and a second oligomeric compound having a region complementary to the first oligomeric compound. The first oligomeric compound of such double stranded antisense compounds typically comprises or consists of a modified oligonucleotide and optionally a conjugate group. The oligonucleotide of the second oligomeric compound of such a double-stranded antisense compound may be modified or unmodified. Either or both oligomeric compounds of a double-stranded antisense compound may comprise a conjugate group. The oligomeric compounds of double-stranded antisense compounds may include non-complementary overhanging nucleosides.

Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, siRNAs, microRNA targeting oligonucleotides, and single-stranded RNAi compounds, such as small hairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNA mimics.

In certain embodiments, a compound described herein has a nucleobase sequence that, when written in the 5′ to 3′ direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted.

In certain embodiments, a compound described herein comprises an oligonucleotide 12 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 12 to 22 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 14 to 30 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 14 to 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 15 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 15 to 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 to 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 to 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 18 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 18 to 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 20 to 30 linked subunits in length. In other words, such oligonucleotides are 12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to 20 subunits, or 20 to 30 subunits in length, respectively. In certain embodiments, a compound described herein comprises an oligonucleotide 14 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 18 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 20 linked subunits in length. In other embodiments, a compound described herein comprises an oligonucleotide 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. In certain such embodiments, the compound described herein comprises an oligonucleotide 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked subunits in length, or a range defined by any two of the above values. In some embodiments the linked subunits are nucleotides, nucleosides, or nucleobases.

In certain embodiments, the compound may further comprise additional features or elements, such as a conjugate group, that are attached to the oligonucleotide. In certain embodiments, such compounds are antisense compounds. In certain embodiments, such compounds are oligomeric compounds. In embodiments where a conjugate group comprises a nucleoside (i.e. a nucleoside that links the conjugate group to the oligonucleotide), the nucleoside of the conjugate group is not counted in the length of the oligonucleotide.

In certain embodiments, compounds may be shortened or truncated. For example, a single subunit may be deleted from the 5′ end (5′ truncation), or alternatively from the 3′ end (3′ truncation). A shortened or truncated compound targeted to a IRF5 nucleic acid may have two subunits deleted from the 5′ end, or alternatively, may have two subunits deleted from the 3′ end of the compound. Alternatively, the deleted nucleosides may be dispersed throughout the compound.

When a single additional subunit is present in a lengthened compound, the additional subunit may be located at the 5′ or 3′ end of the compound. When two or more additional subunits are present, the added subunits may be adjacent to each other, for example, in a compound having two subunits added to the 5′ end (5′ addition), or alternatively, to the 3′ end (3′ addition) of the compound. Alternatively, the added subunits may be dispersed throughout the compound.

It is possible to increase or decrease the length of a compound, such as an oligonucleotide, and/or introduce mismatch bases without eliminating activity (Woolf et al. Proc. Natl. Acad. Sci. USA 1992, 89:7305-7309; Gautschi et al. J. Natl. Cancer Inst. March 2001, 93:463-471; Maher and Dolnick Nuc. Acid. Res. 1998, 16:3341-3358). However, seemingly small changes in oligonucleotide sequence, chemistry and motif can make large differences in one or more of the many properties required for clinical development (Seth et al. J. Med. Chem. 2009, 52, 10; Egli et al. J. Am. Chem. Soc. 2011, 133, 16642).

In certain embodiments, compounds described herein are interfering RNA compounds (RNAi), which include double-stranded RNA compounds (also referred to as short-interfering RNA or siRNA) and single-stranded RNAi compounds (or ssRNA). Such compounds work at least in part through the RISC pathway to degrade and/or sequester a target nucleic acid (thus, include microRNA/microRNA-mimic compounds). As used herein, the term siRNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence-specific RNAi, for example, short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term “RNAi” is meant to be equivalent to other terms used to describe sequence-specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics.

In certain embodiments, a compound described herein can comprise any of the oligonucleotide sequences targeted to IRF5 described herein. In certain embodiments, the compound can be double-stranded. In certain embodiments, the compound comprises a first strand comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion of any one of SEQ ID NOs: 37-1356 and a second strand. In certain embodiments, the compound comprises a first strand comprising the nucleobase sequence of any one of SEQ ID NOs: 37-1356 and a second strand. In certain embodiments, the compound comprises ribonucleotides in which the first strand has uracil (U) in place of thymine (T) in any one of SEQ ID NOs: 37-1356. In certain embodiments, the compound comprises (i) a first strand comprising a nucleobase sequence complementary to the site on IRF5 to which any of SEQ ID NOs: 37-1356 is targeted, and (ii) a second strand. In certain embodiments, the compound comprises one or more modified nucleotides in which the 2′ position of the sugar contains a halogen (such as fluorine group; 2′-F) or contains an alkoxy group (such as a methoxy group; 2′-OMe). In certain embodiments, the compound comprises at least one 2′-F sugar modification and at least one 2′-OMe sugar modification. In certain embodiments, the at least one 2′-F sugar modification and at least one 2′-OMe sugar modification are arranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strand of the dsRNA compound. In certain embodiments, the compound comprises one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The compounds may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the compound contains one or two capped strands, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000.

In certain embodiments, the first strand of the compound is an siRNA guide strand and the second strand of the compound is an siRNA passenger strand. In certain embodiments, the second strand of the compound is complementary to the first strand. In certain embodiments, each strand of the compound is 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides in length. In certain embodiments, the first or second strand of the compound can comprise a conjugate group.

In certain embodiments, a compound described herein can comprise any of the oligonucleotide sequences targeted to IRF5 described herein. In certain embodiments, the compound is single stranded. In certain embodiments, such a compound is a single-stranded RNAi (ssRNAi) compound. In certain embodiments, the compound comprises at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion of any one of SEQ ID NOs: 37-1356. In certain embodiments, the compound comprises the nucleobase sequence of any one of SEQ ID NOs: 37-1356. In certain embodiments, the compound comprises ribonucleotides in which uracil (U) is in place of thymine (T) in any one of SEQ ID NOs: 37-1356. In certain embodiments, the compound comprises a nucleobase sequence complementary to the site on IRF5 to which any of SEQ ID NOs: 37-1356 is targeted. In certain embodiments, the compound comprises one or more modified nucleotides in which the 2′ position in the sugar contains a halogen (such as fluorine group; 2′-F) or contains an alkoxy group (such as a methoxy group; 2′-OMe). In certain embodiments, the compound comprises at least one 2′-F sugar modification and at least one 2′-OMe sugar modification. In certain embodiments, the at least one 2′-F sugar modification and at least one 2′-OMe sugar modification are arranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strand of the compound. In certain embodiments, the compound comprises one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The compounds may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the compound contains a capped strand, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000. In certain embodiments, the compound consists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. In certain embodiments, the compound can comprise a conjugate group.

Certain Mechanisms

In certain embodiments, compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, compounds described herein are antisense compounds. In certain embodiments, compounds comprise oligomeric compounds. In certain embodiments, compounds described herein are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity. In certain embodiments, compounds described herein selectively affect one or more target nucleic acid. Such compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in a significant undesired antisense activity.

In certain antisense activities, hybridization of a compound described herein to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid. For example, certain compounds described herein result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, compounds described herein are sufficiently “DNA-like” to elicit RNase H activity. Further, in certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

In certain antisense activities, compounds described herein or a portion of the compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein result in cleavage of the target nucleic acid by Argonaute. Compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA).

In certain embodiments, hybridization of compounds described herein to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain such embodiments, hybridization of the compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of the compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain such embodiments, hybridization of the compound to a target nucleic acid results in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and/or a phenotypic change in a cell or animal.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

In certain embodiments, compounds described herein comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from an mRNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target RNA is an mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron.

Nucleotide sequences that encode IRF5 include, without limitation, the following: RefSeq or GENBANK Accession No. U51127.1 (incorporated by reference, disclosed herein as SEQ ID NO: 4); GENBANK Accession No. NT 007933.14 truncated from nucleotides 53761170 to U.S. Pat. No. 53,774,065 (incorporated by reference, disclosed herein as SEQ ID NO: 2); GENBANK Accession No. DC427600.1 (incorporated by reference, disclosed herein as SEQ ID NO: 5); GENBANK Accession No. NM_001098627.3 (incorporated by reference, disclosed herein as SEQ ID NO: 1); GENBANK Accession No. NM_001098629.2 (incorporated by reference, disclosed herein as SEQ ID NO: 3); GENBANK Accession No. NM_001098630.2 (incorporated by reference, disclosed herein as SEQ ID NO: 6); GENBANK Accession No. NM_001242452.2 (incorporated by reference, disclosed herein as SEQ ID NO: 7); GENBANK Accession No. NM_032643.4 (incorporated by reference, disclosed herein as SEQ ID NO: 8); and GENBANK Accession No. NC_000007.14 truncated from nucleotides 128935001 to 128953000 (incorporated by reference, disclosed herein as SEQ ID NO: 9).

Hybridization

In some embodiments, hybridization occurs between a compound disclosed herein and a IRF5 nucleic acid. The most common mechanism of hybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules.

Hybridization can occur under varying conditions. Hybridization conditions are sequence-dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized.

Methods of determining whether a sequence is specifically hybridizable to a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein are specifically hybridizable with a IRF5 nucleic acid.

Complementarity

An oligonucleotide is said to be complementary to another nucleic acid when the nucleobase sequence of such oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Nucleobase matches or complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) and guanine (G), unless otherwise specified. Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches. An oligonucleotide is fully complementary or 100% complementary when such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

In certain embodiments, compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, compounds described herein are antisense compounds. In certain embodiments, compounds comprise oligomeric compounds. Non-complementary nucleobases between a compound and a IRF5 nucleic acid may be tolerated provided that the compound remains able to specifically hybridize to a target nucleic acid. Moreover, a compound may hybridize over one or more segments of a IRF5 nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).

In certain embodiments, the compounds provided herein, or a specified portion thereof are at least, or are up to 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a IRF5 nucleic acid, a target region, target segment, or specified portion thereof. In certain embodiments, the compounds provided herein, or a specified portion thereof, are 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any number in between these ranges, complementary to a IRF5 nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of a compound with a target nucleic acid can be determined using routine methods.

For example, a compound in which 18 of 20 nucleobases of the compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining non-complementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, a compound which is 18 nucleobases in length having four non-complementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid. Percent complementarity of a compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489).

In certain embodiments, compounds described herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, or specified portion thereof. For example, a compound may be fully complementary to a IRF5 nucleic acid, or a target region, or a target segment or target sequence thereof. As used herein, “fully complementary” means each nucleobase of a compound is complementary to the corresponding nucleobase of a target nucleic acid. For example, a 20 nucleobase compound is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the compound. “Fully complementary” can also be used in reference to a specified portion of the first and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase compound can be “fully complementary” to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase compound is fully complementary to the target sequence if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the compound. At the same time, the entire 30 nucleobase compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the compound are also complementary to the target sequence.

In certain embodiments, compounds described herein comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain such embodiments, antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount. Thus, in certain such embodiments, selectivity of the compound is improved. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5′-end of the gap region. In certain such embodiments, the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of the gap region. In certain such embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5′-end of the wing region. In certain such embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-end of the wing region. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide not having a gapmer motif. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. In certain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

The location of a non-complementary nucleobase may be at the 5′ end or 3′ end of the compound. Alternatively, the non-complementary nucleobase or nucleobases may be at an internal position of the compound. When two or more non-complementary nucleobases are present, they may be contiguous (i.e. linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer oligonucleotide.

In certain embodiments, compounds described herein that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a IRF5 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than κ, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a IRF5 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein also include those which are complementary to a portion of a target nucleic acid. As used herein, “portion” refers to a defined number of contiguous (i.e. linked) nucleobases within a region or segment of a target nucleic acid. A “portion” can also refer to a defined number of contiguous nucleobases of a compound. In certain embodiments, the compounds, are complementary to at least an 8 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 9 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 10 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least an 11 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 13 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 14 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 15 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 16 nucleobase portion of a target segment. Also contemplated are compounds that are complementary to at least a 9, 10, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values.

Identity

The compounds provided herein may also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific ION number, or portion thereof. In certain embodiments, compounds described herein are antisense compounds or oligomeric compounds. In certain embodiments, compounds described herein are modified oligonucleotides. As used herein, a compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the compounds described herein as well as compounds having non-identical bases relative to the compounds provided herein also are contemplated. The non-identical bases may be adjacent to each other or dispersed throughout the compound. Percent identity of an compound is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared.

In certain embodiments, compounds described herein, or portions thereof, are, or are at least, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the compounds or SEQ ID NOs, or a portion thereof, disclosed herein. In certain embodiments, compounds described herein are about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, or any percentage between such values, to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific ION number, or portion thereof, in which the compounds comprise an oligonucleotide having one or more mismatched nucleobases. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. In certain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

In certain embodiments, compounds described herein comprise or consist of antisense compounds. In certain embodiments, a portion of the antisense compound is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

In certain embodiments, compounds described herein comprise or consist of oligonucleotides. In certain embodiments, a portion of the oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

Certain Modified Compounds

In certain embodiments, compounds described herein comprise or consist of oligonucleotides consisting of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA (i.e., comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage).

A. Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase.

1. Modified Sugar Moieties

In certain embodiments, sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclic modified furanosyl sugar moieties comprising one or more acyclic substituent, including, but not limited, to substituents at the 2′, 4′, and/or 5′ positions. In certain embodiments, the furanosyl sugar moiety is a ribosyl sugar moiety. In certain embodiments, one or more acyclic substituent of non-bicyclic modified sugar moieties is branched. Examples of 2′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or “O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE”). In certain embodiments, 2′-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF₃, OCF₃, O—C₁-C₁₀ alkoxy, O—C₁-C₁₀ substituted alkoxy, O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl, N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl, S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) or OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat. No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al., U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groups suitable for linearly non-bicyclic modified sugar moieties include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. Examples of 5′-substituent groups suitable for non-bicyclic modified sugar moieties include, but are not limited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certain embodiments, non-bicyclic modified sugars comprise more than one non-bridging sugar substituent, for example, 2′-F-5′-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclic modified nucleoside comprises a sugar moiety comprising a linear 2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂, CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substituted acetamide (OCH₂C(═O)—N(R_(m))(R_(n))), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclic modified nucleoside comprises a sugar moiety comprising a linear 2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂, O(CH₂)₂N(CH₃)₂, and OCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclic modified nucleoside comprises a sugar moiety comprising a linear 2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

Nucleosides comprising modified sugar moieties, such as non-bicyclic modified sugar moieties, are referred to by the position(s) of the substitution(s) on the sugar moiety of the nucleoside. For example, nucleosides comprising 2′-substituted or 2′-modified sugar moieties are referred to as 2′-substituted nucleosides or 2′-modified nucleosides.

Certain modified sugar moieties comprise a bridging sugar substituent that forms a second ring resulting in a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4′ and the 2′ furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. Examples of such 4′ to 2′ bridging sugar substituents include, but are not limited to: 4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, 4′-CH₂—O-2′ (“LNA”), 4′-CH₂—S-2′, 4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt” when in the S configuration), 4′-CH₂—O—CH₂-2′, 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′, 4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O-2′, wherein each R, R_(a), and R_(b), is, independently, H, a protecting group, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No. 7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprise from 1 to 4 linked groups independently selected from: —[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)—O—, —C(R_(a))═C(R_(b))—, —C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—, —S(═O)_(x)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b), is, independently, H, a protecting group, hydroxyl, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical, substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃, COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), or sulfoxyl (S(═O)-J₁); and each J₁ and J₂ is, independently, H, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl, substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U S. A., 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129, 8362-8379; Elayadi et al., Curr. Opinion Invens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel et al., U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490, Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133, Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No. 6,525,191, Torsten et al., WO 2004/106356, Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; and Migawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. When the positions of specific bicyclic nucleosides (e.g., LNA or cEt) are identified in exemplified embodiments herein, they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. In certain such embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4′-sulfur atom and a substitution at the 2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include, but are not limited to, hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“MNA”) (see e.g., Leumann, C J. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoro HNA:

(“F-HNA”, see e.g., Swayze et al., U.S. Pat. No. 8,088,904; Swayze et al., U.S. Pat. No. 8,440,803; and Swayze et al., U.S. Pat. No. 9,005,906) F-HNA can also be referred to as a F-THP or 3′-fluoro tetrahydropyran, and nucleosides comprising additional modified THP compounds having the formula:

wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide or one of T₃ and T₄ is an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protecting group, a linked conjugate group, or a 5′ or 3′-terminal group; q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, or substituted C₂-C₆ alkynyl; and each of R₁ and R₂ is independently selected from among: hydrogen, halogen, substituted or unsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂, NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃ is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided wherein q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, in certain embodiments, R₁ is methoxy and R₂ is H, and in certain embodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example, by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include, but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US2013/130378.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

2. Modified Nucleobases

Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Such nucleobase modifications can impart nuclease stability, binding affinity or some other beneficial biological property to antisense compounds.

In certain embodiments, compounds described herein comprise modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that does not comprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C═C—CH₃) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above noted modified nucleobases, as well as other modified nucleobases include without limitation, Manoharan et al., US2003/0158403, Manoharan et al., US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540; Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook et al., U.S. Pat. No. 6,166,199; and Matteucci et al., U.S. Pat. No. 6,005,096.

In certain embodiments, compounds targeted to a IRF5 nucleic acid comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

Modified Internucleoside Linkages

The naturally occurring internucleoside linkage of RNA and DNA is a 3′ to 5′ phosphodiester linkage. In certain embodiments, compounds described herein having one or more modified, i.e. non-naturally occurring, internucleoside linkages are often selected over compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.

Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

In certain embodiments, compounds targeted to a IRF5 nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage.

In certain embodiments, compounds described herein comprise oligonucleotides. Oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known.

In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include, but are not limited to, phosphates, which contain a phosphodiester bond (“P═O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), and phosphorodithioates (“HS-P═S”). Representative non-phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (—CH₂—N(CH₃)—O—CH₂), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH₂—O—); and N,N′-dimethylhydrazine (—CH₂—N(CH₃)—N(CH₃)—). Modified internucleoside linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.

Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH₂—N(CH₃)—O-5′), amide-3 (3′-CH₂—C(═O)—N(H)-5′), amide-4 (3′-CH₂—N(H)—C(═O)-5′), formacetal (3′-O—CH₂—O-5′), methoxypropyl, and thioformacetal (3′-S—CH₂—O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See, for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH₂ component parts.

In certain embodiments, oligonucleotides comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, internucleoside linkages are arranged in a gapped motif. In such embodiments, the internucleoside linkages in each of two wing regions are different from the internucleoside linkages in the gap region. In certain embodiments, the internucleoside linkages in the wings are phosphodiester and the internucleoside linkages in the gap are phosphorothioate. The nucleoside motif is independently selected, so such oligonucleotides having a gapped internucleoside linkage motif may or may not have a gapped nucleoside motif and, if it does have a gapped nucleoside motif, the wing and gap lengths may or may not be the same.

In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate.

In certain embodiments, the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least block of at least one 12 consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3′ end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3′ end of the oligonucleotide.

In certain embodiments, oligonucleotides comprise one or more methylphosphonate linkages. In certain embodiments, oligonucleotides having a gapmer nucleoside motif comprise a linkage motif comprising all phosphorothioate linkages except for one or two methylphosphonate linkages. In certain embodiments, one methylphosphonate linkage is in the central gap of an oligonucleotide having a gapmer nucleoside motif.

In certain embodiments, it is desirable to arrange the number of phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages to maintain nuclease resistance. In certain embodiments, it is desirable to arrange the number and position of phosphorothioate internucleoside linkages and the number and position of phosphodiester internucleoside linkages to maintain nuclease resistance. In certain embodiments, the number of phosphorothioate internucleoside linkages may be decreased and the number of phosphodiester internucleoside linkages may be increased. In certain embodiments, the number of phosphorothioate internucleoside linkages may be decreased and the number of phosphodiester internucleoside linkages may be increased while still maintaining nuclease resistance. In certain embodiments, it is desirable to decrease the number of phosphorothioate internucleoside linkages while retaining nuclease resistance. In certain embodiments, it is desirable to increase the number of phosphodiester internucleoside linkages while retaining nuclease resistance.

3. Certain Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. Oligonucleotides can have a motif, e.g. a pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).

a. Certain Sugar Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which comprises two external regions or “wings” and a central or internal region or “gap”. The three regions of a gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguous sequence of nucleosides, wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside of the 3′-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleosides having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5′-wing differs from the sugar motif of the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides. In certain embodiments, the wings of a gapmer comprise 2-5 nucleosides. In certain embodiments, the wings of a gapmer comprise 3-5 nucleosides. In certain embodiments, the nucleosides of a gapmer are all modified nucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides. In certain embodiments, the gap of a gapmer comprises 7-10 nucleosides. In certain embodiments, the gap of a gapmer comprises 8-10 nucleosides. In certain embodiments, the gap of a gapmer comprises 10 nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer is an unmodified 2′-deoxy nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In such embodiments, the nucleosides on the gap side of each wing/gap junction are unmodified 2′-deoxy nucleosides and the nucleosides on the wing sides of each wing/gap junction are modified nucleosides. In certain such embodiments, each nucleoside of the gap is an unmodified 2′-deoxy nucleoside. In certain such embodiments, each nucleoside of each wing is a modified nucleoside.

In certain embodiments, a modified oligonucleotide has a fully modified sugar motif wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif wherein each nucleoside of the region comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified comprises the same 2′-modification.

b. Certain Nucleobase Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosines.

In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosyl moiety. In certain embodiments, the modified nucleobase is selected from: a 2-thiopyrimidine and a 5-propynepyrimidine.

c. Certain Internucleoside Linkage Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and/or unmodified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, essentially each internucleoside linking group is a phosphate internucleoside linkage (P═O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate (P═S). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is independently selected from a phosphorothioate and phosphate internucleoside linkage. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified. In certain such embodiments, some or all of the internucleoside linkages in the wings are unmodified phosphate linkages. In certain embodiments, the terminal internucleoside linkages are modified. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain such embodiments, all of the phosphorothioate linkages are stereorandom. In certain embodiments, all of the phosphorothioate linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp, Sp, Rp motif. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such internucleoside linkage motifs.

4. Certain Modified Oligonucleotides

In certain embodiments, compounds described herein comprise modified oligonucleotides. In certain embodiments, the above modifications (sugar, nucleobase, internucleoside linkage) are incorporated into a modified oligonucleotide. In certain embodiments, modified oligonucleotides are characterized by their modification, motifs, and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region of the sugar motif. Likewise, such gapmer oligonucleotides may comprise one or more modified nucleobases independent of the gapmer pattern of the sugar modifications. Furthermore, in certain instances, an oligonucleotide is described by an overall length or range and by lengths or length ranges of two or more regions (e.g., a regions of nucleosides having specified sugar modifications). In such circumstances, it may be possible to select numbers for each range that result in an oligonucleotide having an overall length falling outside the specified range. In such circumstances, both elements must be satisfied. For example, in certain embodiments, a modified oligonucleotide consists of 15-20 linked nucleosides and has a sugar motif consisting of three regions, A, B, and C, wherein region A consists of 2-6 linked nucleosides having a specified sugar motif, region B consists of 6-10 linked nucleosides having a specified sugar motif, and region C consists of 2-6 linked nucleosides having a specified sugar motif. Such embodiments do not include modified oligonucleotides where A and C each consist of 6 linked nucleosides and B consists of 10 linked nucleosides (even though those numbers of nucleosides are permitted within the requirements for A, B, and C) because the overall length of such oligonucleotide will be 22, which exceeds the upper limit of the overall length of the modified oligonucleotide (20). Herein, if a description of an oligonucleotide is silent with respect to one or more parameters, such parameter is not limited. Thus, a modified oligonucleotide described only as having a gapmer sugar motif without further description may have any length, internucleoside linkage motif, and nucleobase motif. Unless otherwise indicated, all modifications are independent of nucleobase sequence.

Certain Conjugated Compounds

In certain embodiments, the compounds described herein comprise or consist of an oligonucleotide (modified or unmodified) and, optionally, one or more conjugate groups and/or terminal groups. Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2′-position of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3′ and/or 5′-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 3′-end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5 ‘-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 5’-end of oligonucleotides.

In certain embodiments, the oligonucleotide is modified. In certain embodiments, the oligonucleotide of a compound has a nucleobase sequence that is complementary to a target nucleic acid. In certain embodiments, oligonucleotides are complementary to a messenger RNA (mRNA). In certain embodiments, oligonucleotides are complementary to a pre-mRNA. In certain embodiments, oligonucleotides are complementary to a sense transcript.

Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.

Compositions and Methods for Formulating Pharmaceutical Compositions

Compounds described herein may be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

Certain embodiments provide pharmaceutical compositions comprising one or more compounds or a salt thereof. In certain embodiments, the compounds are antisense compounds or oligomeric compounds. In certain embodiments, the compounds comprise or consist of a modified oligonucleotide. In certain such embodiments, the pharmaceutical composition comprises a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises a sterile saline solution and one or more compound. In certain embodiments, such pharmaceutical composition consists of a sterile saline solution and one or more compound. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises one or more compound and sterile water. In certain embodiments, a pharmaceutical composition consists of one compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises one or more compounds and phosphate-buffered saline (PBS). In certain embodiments, a pharmaceutical composition consists of one or more compound and sterile PBS. In certain embodiments, the sterile PBS is pharmaceutical grade PBS. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

A compound described herein targeted to IRF5 nucleic acid can be utilized in pharmaceutical compositions by combining the compound with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising a compound targeted to IRF5 nucleic acid and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of a modified oligonucleotide provided herein.

Pharmaceutical compositions comprising compounds provided herein encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. In certain embodiments, the compounds are antisense compounds or oligomeric compounds. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at one or both ends of a compound which are cleaved by endogenous nucleases within the body, to form the active compound.

In certain embodiments, the compounds or compositions further comprise a pharmaceutically acceptable carrier or diluent.

Certain Selected Compounds

Approximately 1,320 newly designed compounds of various lengths, chemistries, and motifs were tested for their effect on human IRF5 mRNA in vitro in several cell types (Examples 1 and 2). Of 1,320 compounds tested for potency at a single dose in vitro, over 110 selected compounds were tested for dose dependent inhibition in THP-1 cells, as well as in KARPAS-229 cells (Example 3).

These oligonucleotides were then tested for tolerability in preclinical rodent models (Examples 4 and 5). Body weights and organ weights, liver function markers (such as alanine transaminase, aspartate transaminase and bilirubin), hematology markers (such as hemoglobin and hematocrit levels, as well as individual blood cell counts), and kidney function markers (such as BUN and creatinine) were measured. Of the over 110 compounds tested by dose response assays, 53 compounds were further screened for tolerability in a CD-1 mouse model. Nineteen oligonucleotides were further screened in the Sprague-Dawley rat model.

Twelve compounds were then selected and tested in a mouse xenograft model, where the mice were inoculated with human non-Hodgkin's Large Cell Lymphoma (KARPAS-229) cells and treated with the compounds (Example 6). The efficacy and tolerability of the compounds were then tested. Eight compounds were then selected to be tested for efficacy at two separate doses in an IRF5 transgenic mouse model (Example 7).

IONs 729018, 728958, 785525, 785674, 785675, 786503, 786524, and 786548 were tested for tolerability in cynomolgus monkeys (Example 8). Treatment with the compounds was well tolerated in the monkeys, in particular, treatment with ION 729018. Further analysis was done with these compounds, including measuring for viscosity, evaluation of proinflammatory effects, and dose-dependent inhibition confirmation assays.

Modified oligonucleotides with different chemistry modifications were also designed overlapping the target regions of three compounds, IONs 729018, 786503, and 785675 (Example 13). These newly designed compounds along with the three parent oligonucleotides were tested in a multi-dose assay. Many of the newly designed compounds demonstrated strong efficacy in inhibiting IRF5.

Accordingly, provided herein are compounds with any one or more of the improved properties. In certain embodiments, the compounds as described herein are potent and tolerable.

EXAMPLES

The Examples below describe the screening process to identify lead compounds targeted to IRF5. ION 728958, 729018, 785525, 785674, 785675, 786503, 786524, and 786548 resulted in high potency and tolerability. For instance, ION 729018 exhibited high potency and tolerability.

Non-Limiting Disclosure and Incorporation by Reference

Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH for the natural 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) for natural uracil of RNA).

Accordingly, nucleic acid sequences provided herein, including, but not limited to, those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to, such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligonucleotide having the nucleobase sequence “ATCGATCG” encompasses any oligonucleotides having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and compounds having other modified nucleobases, such as “ATmCGAUCG,” wherein mC indicates a cytosine base comprising a methyl group at the 5-position.

Certain compounds described herein (e.g. modified oligonucleotides) have one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as a or (3, such as for sugar anomers, or as (D) or (L), such as for amino acids, etc. Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds. Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms. Likewise, all tautomeric forms of the compounds provided herein are included unless otherwise indicated. Unless otherwise indicated, oligomeric compounds and modified oligonucleotides described herein are intended to include corresponding salt forms.

Compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the ¹H hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to: ²H or ³H in place of ¹H, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S.

While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety.

Example 1: Antisense Inhibition of Human IRF5 in THP-1 Cells by cEt Gapmers

Modified oligonucleotides were designed to target an IRF5 nucleic acid and were tested for their effect on IRF5 RNA levels in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

The newly designed modified oligonucleotides in the Tables below were designed as 3-10-3 cEt gapmers. The gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2′-deoxynucleosides and is flanked by wing segments on the 5′ direction and the 3′ direction comprising three nucleosides each. Each nucleoside in the 5′ wing segment and each nucleoside in the 3′ wing segment has a cEt sugar modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P═S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted in the human gene sequence. Most of the modified oligonucleotide listed in the Tables below are targeted to either human IRF5 mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001098627.3) or to human IRF5 genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007933.14 truncated from nucleotides 53761170 to 53774065). In addition, a small number of modified oligonucleotides are targeted to IRF5 mRNA designated herein as SEQ ID No: 3 (GENBANK Accession No. NM_001098629.1). ‘N/A’ indicates that the modified oligonucleotide does not target that gene sequence with 100% complementarity.

Cultured THP-1 cells at a density of 30,000 cells per well were transfected using electroporation with 2,000 nM of modified oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and IRF5 RNA levels were measured by quantitative real-time RTPCR. Human primer probe set HTS4167 (forward sequence GCCAAGGAGACAGGGAAATACA, designated herein as SEQ ID NO: 11; reverse sequence GCAGGTTGGCCTTCCACTT; designated herein as SEQ ID NO: 12; probe sequence CGAAGGCGTGGATGAAGCCGATC, designated herein as SEQ ID NO: 13) was used to measure RNA levels. IRF5 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of IRF5 relative to untreated control cells. As used herein, a value of ‘0’ indicates that treatment with the modified oligonucleotide did not inhibit IRF5 mRNA levels. ‘N.D.’ indicates that the % inhibition is not defined for that modified oligonucleotide in that experiment. Activity of that modified oligonucleotide may be defined in a different experiment.

TABLE 1 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 665773 N/A N/A  4534  4549 GGTTCATGGCAGAGGG 46  37 665775 N/A N/A  4545  4560 TGGGATGGACTGGTTC 35  38 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 70  39 728374 N/A N/A   402   417 CCGCCAACCTGCCGGG  3  40 728375 N/A N/A   404   419 GTCCGCCAACCTGCCG  0  41 728376 N/A N/A   408   423 GCCGGTCCGCCAACCT 12  42 728377 N/A N/A   410   425 CCGCCGGTCCGCCAAC  0  43 728378 N/A N/A   412   427 TCCCGCCGGTCCGCCA  7  44 728379 N/A N/A   414   429 CCTCCCGCCGGTCCGC  7  45 728380 N/A N/A   416   431 CGCCTCCCGCCGGTCC 18  46 728381 N/A N/A   418   433 TGCGCCTCCCGCCGGT  9  47 728382 N/A N/A   430   445 CTCTGCCCAGGCTGCG 17  48 728383 N/A N/A   440   455 CCAAGCTGAGCTCTGC 29  49 728384 N/A N/A   442   457 GACCAAGCTGAGCTCT 22  50 728385 N/A N/A   445   460 CGGGACCAAGCTGAGC 17  51 728386 N/A N/A   447   462 GGCGGGACCAAGCTGA  0  52 728387 N/A N/A   450   465 GGCGGCGGGACCAAGC  6  53 728388 N/A N/A   459   474 CACCGGCCGGGCGGCG  0  54 728389 N/A N/A   461   476 AGCACCGGCCGGGCGG  0  55 728390 N/A N/A   463   478 GGAGCACCGGCCGGGC  9  56 728391 N/A N/A   466   481 CAGGGAGCACCGGCCG 15  57 728392 N/A N/A   468   483 GCCAGGGAGCACCGGC  0  58 728393 N/A N/A   470   485 GCGCCAGGGAGCACCG  4  59 728394 N/A N/A   472   487 CTGCGCCAGGGAGCAC  4  60 728395 N/A N/A   474   489 GGCTGCGCCAGGGAGC N.D.  61 728396 N/A N/A   476   491 GTGGCTGCGCCAGGGA  8  62 728397 N/A N/A   492   507 TCTGCGGTGCGCCTGC 25  63 728398 N/A N/A   494   509 TGTCTGCGGTGCGCCT 31  64 728401  210  225  4535  4550 TGGTTCATGGCAGAGG 50  65 728402  211  226  4536  4551 CTGGTTCATGGCAGAG 44  66 728403  213  228  4538  4553 GACTGGTTCATGGCAG 25  67 728404  214  229  4539  4554 GGACTGGTTCATGGCA 32  68 728405  216  231  4541  4556 ATGGACTGGTTCATGG 49  69 728406  217  232  4542  4557 GATGGACTGGTTCATG 42  70 728407  218  233  4543  4558 GGATGGACTGGTTCAT 47  71 728408  219  234  4544  4559 GGGATGGACTGGTTCA 53  72 728409  223  238  4548  4563 CACTGGGATGGACTGG 40  73 728410  225  240  4550  4565 GCCACTGGGATGGACT 16  74 728411  227  242  4552  4567 GAGCCACTGGGATGGA 40  75 728412  253  268  4578  4593 CAGCCGCACGCGGCGG  6  76 728413  255  270  4580  4595 TTCAGCCGCACGCGGC 44  77 728414  257  272  4582  4597 GCTTCAGCCGCACGCG 27  78 728415  259  274  4584  4599 GGGCTTCAGCCGCACG  8  79 728416  284  299  4609  4624 AGCTGTTCACCTGGGC  5  80 728417  286  301  4611  4626 GCAGCTGTTCACCTGG  3  81 728418  288  303  4613  4628 TGGCAGCTGTTCACCT  0  82 728419  290  305  4615  4630 ACTGGCAGCTGTTCAC  5  83 728420  292  307  4617  4632 GTACTGGCAGCTGTTC  0  84 728421  294  309  4619  4634 GGGTACTGGCAGCTGT  9  85 728422  296  311  4621  4636 CTGGGTACTGGCAGCT  0  86 728423  298  313  4623  4638 CCCTGGGTACTGGCAG 24  87 728424  300  315  4625  4640 AGCCCTGGGTACTGGC  0  88 728425  302  317  4627  4642 GAAGCCCTGGGTACTG  0  89 728426  304  319  4629  4644 TTGAAGCCCTGGGTAC 11  90 728427  306  321  4631  4646 CATTGAAGCCCTGGGT 13  91 728428  308  323  4633  4648 CCCATTGAAGCCCTGG 15  92 728429  310  325  4635  4650 GACCCATTGAAGCCCT 14  93 728430  312  327  4637  4652 TTGACCCATTGAAGCC 11  94 728431  314  329  4639  4654 CGTTGACCCATTGAAG  0  95 728432  316  331  4641  4656 CCCGTTGACCCATTGA 25  96 728433  318  333  4643  4658 TCCCCGTTGACCCATT  6  97 728434  320  335  4645  4660 TTTCCCCGTTGACCCA 20  98 728435  322  337  4647  4662 CTTTTCCCCGTTGACC 12  99 728436  324  339  4649  4664 TTCTTTTCCCCGTTGA 13 100 728437  326  341  4651  4666 ATTTCTTTTCCCCGTT  7 101 728438  328  343  4653  4668 TAATTTCTTTTCCCCG 19 102 728439  356  371  4681  4696 TTGTGGCATGCCTCCA 25 103 728440  358  373  4683  4698 CCTTGTGGCATGCCTC 31 104 728441  360  375  4685  4700 TGCCTTGTGGCATGCC  7 105 728442  362  377  4687  4702 CATGCCTTGTGGCATG  5 106 728443  364  379  4689  4704 ACCATGCCTTGTGGCA  5 107 728444  366  381  4691  4706 GGACCATGCCTTGTGG  6 108 728445  368  383  4693  4708 TGGGACCATGCCTTGT 10 109 728446  371  386  4696  4711 GGCTGGGACCATGCCT  0 110 728447  377  392  4702  4717 CGTCCTGGCTGGGACC  2 111 728448  380  395  4705  4720 CTCCGTCCTGGCTGGG 18 112

TABLE 2 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 665795  385  400  4710  4725 GTTATCTCCGTCCTGG 58 113 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 75  39 728449  381  396  4706  4721 TCTCCGTCCTGGCTGG  2 114 728450  382  397  4707  4722 ATCTCCGTCCTGGCTG  3 115 728451  383  398  4708  4723 TATCTCCGTCCTGGCT  0 116 728452  384  399  4709  4724 TTATCTCCGTCCTGGC 11 117 728453  386  401  4711  4726 TGTTATCTCCGTCCTG 14 118 728454  387  402  4712  4727 GTGTTATCTCCGTCCT 27 119 728455  388  403  4713  4728 GGTGTTATCTCCGTCC 18 120 728456  389  404  4714  4729 TGGTGTTATCTCCGTC 31 121 728457  390  405  4715  4730 ATGGTGTTATCTCCGT 17 122 728458  392  407  4717  4732 AGATGGTGTTATCTCC 50 123 728459  394  409  4719  4734 GAAGATGGTGTTATCT 14 124 728460  396  411  4721  4736 TTGAAGATGGTGTTAT 15 125 728461  398  413  4723  4738 CCTTGAAGATGGTGTT 29 126 728462  400  415 N/A N/A GGCCTTGAAGATGGTG  4 127 728492  490  505  8383  8398 CTTGTTAAGGGCACAG 26 128 728493  491  506  8384  8399 TCTTGTTAAGGGCACA 30 129 728494  492  507  8385  8400 CTCTTGTTAAGGGCAC 45 130 728495  494  509  8387  8402 GGCTCTTGTTAAGGGC 17 131 728496  496  511  8389  8404 CCGGCTCTTGTTAAGG  5 132 728497  498  513  8391  8406 TCCCGGCTCTTGTTAA 14 133 728498  500  515  8393  8408 AGTCCCGGCTCTTGTT 57 134 728499  502  517  8395  8410 GAAGTCCCGGCTCTTG 45 135 728500  504  519  8397  8412 CGGAAGTCCCGGCTCT 43 136 728501  506  521  8399  8414 GGCGGAAGTCCCGGCT 13 137 728502  508  523  8401  8416 GAGGCGGAAGTCCCGG 35 138 728503  510  525  8403  8418 ATGAGGCGGAAGTCCC 23 139 728504  512  527  8405  8420 AGATGAGGCGGAAGTC 21 140 728505  514  529  8407  8422 GTAGATGAGGCGGAAG 29 141 728506  538  553  8431  8446 AGGTGGCATGTCCCGG 41 142 728507  540  555  8433  8448 TGAGGTGGCATGTCCC 40 143 728508  542  557  8435  8450 GCTGAGGTGGCATGTC 33 144 728509  544  559  8437  8452 GGGCTGAGGTGGCATG 44 145 728510  546  561  8439  8454 TAGGGCTGAGGTGGCA 41 146 728511  552  567  8445  8460 ATCTTGTAGGGCTGAG 29 147 728512  554  569  8447  8462 AGATCTTGTAGGGCTG 45 148 728513  556  571  8449  8464 GTAGATCTTGTAGGGC 36 149 728514  572  587  8465  8480 CATTGGAGCAGACCTC  0 150 728515  574  589  8467  8482 GCCATTGGAGCAGACC 13 151 728516  576  591  8469  8484 GGGCCATTGGAGCAGA 15 152 728517  578  593  8471  8486 CAGGGCCATTGGAGCA 15 153 728518  580  595  8473  8488 AGCAGGGCCATTGGAG 13 154 728519  582  597  8475  8490 GGAGCAGGGCCATTGG 24 155 728520  591  606 N/A N/A GAGTCTGTGGGAGCAG 35 156 728521  614  629  8973  8988 AAGAGTAATCCTCAGG 22 157 728522  616  631  8975  8990 AAAAGAGTAATCCTCA  0 158 728523  618  633  8977  8992 CCAAAAGAGTAATCCT  6 159 728524  620  635  8979  8994 CACCAAAAGAGTAATC  1 160

TABLE 3 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 75  39 665985 1981 1996 11546 11561 CTCCTATACAGCTAGG 49 161 665987 1993 2008 11558 11573 CTTAGGCAATTCCTCC 50 162 666005 2159 2174 11724 11739 CTAAGTGCTCACTCAT 64 163 666007 2183 2198 11748 11763 AGCCTTGAGCATCTGA 63 164 666009 2186 2201 11751 11766 GCCAGCCTTGAGCATC 50 165 728956 1977 1992 11542 11557 TATACAGCTAGGCCCC 32 166 728957 1978 1993 11543 11558 CTATACAGCTAGGCCC 43 167 728958 1979 1994 11544 11559 CCTATACAGCTAGGCC 68 168 728959 1980 1995 11545 11560 TCCTATACAGCTAGGC 39 169 728960 1982 1997 11547 11562 CCTCCTATACAGCTAG 48 170 728961 1983 1998 11548 11563 TCCTCCTATACAGCTA 46 171 728962 1984 1999 11549 11564 TTCCTCCTATACAGCT 60 172 728963 1985 2000 11550 11565 ATTCCTCCTATACAGC 35 173 728964 1986 2001 11551 11566 AATTCCTCCTATACAG 28 174 728965 1988 2003 11553 11568 GCAATTCCTCCTATAC 61 175 728966 1989 2004 11554 11569 GGCAATTCCTCCTATA 60 176 728967 1992 2007 11557 11572 TTAGGCAATTCCTCCT 51 177 728968 1994 2009 11559 11574 CCTTAGGCAATTCCTC 64 178 728969 1995 2010 11560 11575 CCCTTAGGCAATTCCT 68 179 728970 1996 2011 11561 11576 ACCCTTAGGCAATTCC 77 180 728971 1998 2013 11563 11578 CCACCCTTAGGCAATT 46 181 728972 2000 2015 11565 11580 GGCCACCCTTAGGCAA 62 182 728973 2003 2018 11568 11583 GTGGGCCACCCTTAGG 58 183 728974 2006 2021 11571 11586 AGAGTGGGCCACCCTT 33 184 728975 2008 2023 11573 11588 CAAGAGTGGGCCACCC 45 185 728976 2010 2025 11575 11590 CACAAGAGTGGGCCAC 37 186 728977 2012 2027 11577 11592 ATCACAAGAGTGGGCC 52 187 728978 2014 2029 11579 11594 CAATCACAAGAGTGGG 59 188 728979 2016 2031 11581 11596 GGCAATCACAAGAGTG 47 189 728980 2033 2048 11598 11613 GTTGCCAGAGGAAATG 13 190 728981 2035 2050 11600 11615 TTGTTGCCAGAGGAAA 15 191 728982 2037 2052 11602 11617 TTTTGTTGCCAGAGGA 19 192 728983 2040 2055 11605 11620 GGCTTTTGTTGCCAGA 17 193 728984 2047 2062 11612 11627 ACACTCTGGCTTTTGT 11 194 728985 2049 2064 11614 11629 CAACACTCTGGCTTTT  0 195 728986 2051 2066 11616 11631 CACAACACTCTGGCTT 44 196 728987 2059 2074 11624 11639 ACTTGGCCCACAACAC  9 197 728988 2061 2076 11626 11641 GGACTTGGCCCACAAC 29 198 728989 2086 2101 11651 11666 CATGCCCTGCAGAGGC 44 199 728990 2095 2110 11660 11675 AATCAGGGCCATGCCC  0 200 728991 2097 2112 11662 11677 GAAATCAGGGCCATGC  9 201 728992 2106 2121 11671 11686 CAAACCAGGGAAATCA 26 202 728993 2108 2123 11673 11688 CTCAAACCAGGGAAAT 51 203 728994 2110 2125 11675 11690 GTCTCAAACCAGGGAA 63 204 728995 2112 2127 11677 11692 GAGTCTCAAACCAGGG 61 205 728996 2114 2129 11679 11694 GTGAGTCTCAAACCAG 71 206 728997 2117 2132 11682 11697 GAAGTGAGTCTCAAAC 58 207 728998 2119 2134 11684 11699 AGGAAGTGAGTCTCAA 68 208 728999 2121 2136 11686 11701 TGAGGAAGTGAGTCTC 20 209 729000 2141 2156 11706 11721 TATCTCAGAGGACAGG 63 210 729001 2143 2158 11708 11723 ATTATCTCAGAGGACA 67 211 729002 2145 2160 11710 11725 ATATTATCTCAGAGGA 61 212 729003 2148 2163 11713 11728 CTCATATTATCTCAGA 64 213 729004 2152 2167 11717 11732 CTCACTCATATTATCT 50 214 729005 2154 2169 11719 11734 TGCTCACTCATATTAT 20 215 729006 2155 2170 11720 11735 GTGCTCACTCATATTA 53 216 729007 2156 2171 11721 11736 AGTGCTCACTCATATT 38 217 729008 2157 2172 11722 11737 AAGTGCTCACTCATAT 44 218 729009 2158 2173 11723 11738 TAAGTGCTCACTCATA 45 219 729010 2160 2175 11725 11740 CCTAAGTGCTCACTCA 63 220 729011 2161 2176 11726 11741 ACCTAAGTGCTCACTC 64 221 729012 2162 2177 11727 11742 TACCTAAGTGCTCACT 34 222 729013 2163 2178 11728 11743 ATACCTAAGTGCTCAC 56 223 729014 2164 2179 11729 11744 GATACCTAAGTGCTCA 60 224 729015 2166 2181 11731 11746 ATGATACCTAAGTGCT 57 225 729016 2168 2183 11733 11748 ATATGATACCTAAGTG 53 226 729017 2170 2185 11735 11750 TGATATGATACCTAAG 46 227 729018 2172 2187 11737 11752 TCTGATATGATACCTA 71 228 729019 2174 2189 11739 11754 CATCTGATATGATACC 63 229 729020 2176 2191 11741 11756 AGCATCTGATATGATA 65 230 729021 2178 2193 11743 11758 TGAGCATCTGATATGA 60 231 729022 2179 2194 11744 11759 TTGAGCATCTGATATG 37 232 729023 2180 2195 11745 11760 CTTGAGCATCTGATAT 36 233 729024 2181 2196 11746 11761 CCTTGAGCATCTGATA 56 234 729025 2182 2197 11747 11762 GCCTTGAGCATCTGAT 54 235 729026 2185 2200 11750 11765 CCAGCCTTGAGCATCT 51 236 729027 2187 2202 11752 11767 TGCCAGCCTTGAGCAT 14 237

TABLE 4 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 665830  680  695  9499  9514 TGAGGCTCAGGCTTGG 65 238 665840  715  730  9755  9770 CGGCTGCAGAGTGGGC 43 239  760  775  9800  9815 665842  717  732  9757  9772 GGCGGCTGCAGAGTGG 43 240  762  777  9802  9817 665843  718  733  9758  9773 GGGCGGCTGCAGAGTG 53 241  763  778  9803  9818 665845  720  735  9760  9775 GTGGGCGGCTGCAGAG 43 242  750  765  9790  9805 665846  721  736  9761  9776 AGTGGGCGGCTGCAGA 28 243  751  766  9791  9806 665847  722  737  9762  9777 GAGTGGGCGGCTGCAG 24 244  752  767  9792  9807 665848  724  739  9764  9779 CAGAGTGGGCGGCTGC 40 245  754  769  9794  9809 665853  725  740  9765  9780 GCAGAGTGGGCGGCTG 11 246  755  770  9795  9810 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 72  39 728525  622  637  8981  8996 TGCACCAAAAGAGTAA 22 247 728526  624  639  8983  8998 CCTGCACCAAAAGAGT 31 248 728527  626  641  8985  9000 CTCCTGCACCAAAAGA 39 249 728528  628  643  8987  9002 CTCTCCTGCACCAAAA 31 250 728529  663  678  9482  9497 AACATCCTCTGCAGCT 29 251 728530  666  681  9485  9500 GGCAACATCCTCTGCA 36 252 728531  668  683  9487  9502 TTGGCAACATCCTCTG 45 253 728532  670  685  9489  9504 GCTTGGCAACATCCTC 53 254 728533  672  687  9491  9506 AGGCTTGGCAACATCC 66 255 728534  675  690  9494  9509 CTCAGGCTTGGCAACA 42 256 728535  678  693  9497  9512 AGGCTCAGGCTTGGCA 60 257 728536  681  696  9500  9515 GTGAGGCTCAGGCTTG 44 258 728537  682  697  9501  9516 TGTGAGGCTCAGGCTT 34 259 728538  684  699 N/A N/A TCTGTGAGGCTCAGGC 41 260 728544 N/A N/A  9690  9705 CAGACTGCACTGCATC 29 261 728545 N/A N/A  9692  9707 GCCAGACTGCACTGCA  8 262 728546 N/A N/A  9694  9709 GGGCCAGACTGCACTG 28 263 728547 N/A N/A  9711  9726 AATAGGGTGTCATGTG  6 264 728548 N/A N/A  9713  9728 AGAATAGGGTGTCATG  0 265 728549 N/A N/A  9715  9730 AAAGAATAGGGTGTCA 17 266 728550 N/A N/A  9717  9732 GTAAAGAATAGGGTGT 14 267 728551 N/A N/A  9719  9734 GAGTAAAGAATAGGGT 24 268 728552 N/A N/A  9721  9736 TTGAGTAAAGAATAGG 12 269 728553 N/A N/A  9723  9738 CTTTGAGTAAAGAATA  8 270 728554 N/A N/A  9725  9740 CTCTTTGAGTAAAGAA  0 271 728555 N/A N/A  9727  9742 TCCTCTTTGAGTAAAG 14 272 728556 N/A N/A  9729  9744 CATCCTCTTTGAGTAA 21 273 728557 N/A N/A  9731  9746 GACATCCTCTTTGAGT 11 274 728558 N/A N/A  9733  9748 TTGACATCCTCTTTGA 32 275 728559 N/A N/A  9735  9750 ACTTGACATCCTCTTT 16 276 728560  699  714  9739  9754 GGCCACTTGACATCCT  6 277 728561  701  716  9741  9756 GCGGCCACTTGACATC 31 278 728562  703  718  9743  9758 GGGCGGCCACTTGACA 13 279 728563  705  720  9745  9760 GTGGGCGGCCACTTGA 40 280 728564  707  722  9747  9762 GAGTGGGCGGCCACTT 12 281 728565  709  724  9749  9764 CAGAGTGGGCGGCCAC 38 282 728566  711  726  9751  9766 TGCAGAGTGGGCGGCC 21 283 728567  726  741  9766  9781 CGCAGAGTGGGCGGCT 18 284 728568  727  742  9767  9782 CCGCAGAGTGGGCGGC 17 285 728569  731  746  9771  9786 GCGGCCGCAGAGTGGG  4 286 728570  733  748  9773  9788 AGGCGGCCGCAGAGTG 20 287 728571  735  750  9775  9790 GTAGGCGGCCGCAGAG 14 288 728572  737  752  9777  9792 GAGTAGGCGGCCGCAG 11 289 728573  739  754  9779  9794 CAGAGTAGGCGGCCGC 25 290 728574  741  756  9781  9796 TGCAGAGTAGGCGGCC 12 291 728575  743  758  9783  9798 GCTGCAGAGTAGGCGG 44 292 728576  745  760  9785  9800 CGGCTGCAGAGTAGGC 37 293 728577  747  762  9787  9802 GGCGGCTGCAGAGTAG 45 294 728578  756  771  9796  9811 TGCAGAGTGGGCGGCT  9 295 728579  764  779  9804  9819 CGGGCGGCTGCAGAGT 61 296 728580  765  780  9805  9820 ACGGGCGGCTGCAGAG 28 297 728581  767  782  9807  9822 CCACGGGCGGCTGCAG 17 298 728582  768  783  9808  9823 ACCACGGGCGGCTGCA 29 299 728583  769  784  9809  9824 CACCACGGGCGGCTGC 26 300 728584  771  786  9811  9826 AGCACCACGGGCGGCT  7 301 728585  773  788  9813  9828 CCAGCACCACGGGCGG 41 302 728586  775  790  9815  9830 ACCCAGCACCACGGGC 19 303 728587  777  792  9817  9832 GGACCCAGCACCACGG 41 304 728588  830  845  9870  9885 AGCCAGCAGGGTTGCC 26 305 728589  832  847  9872  9887 GAAGCCAGCAGGGTTG 16 306 728590  834  849  9874  9889 CTGAAGCCAGCAGGGT 26 307 728591  845  860  9885  9900 AGAGAAGCTCCCTGAA  8 308 728592  849  864  9889  9904 TCAGAGAGAAGCTCCC  3 309

TABLE 5 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 642685 1098 1113 10331 10346 AAGCGCACTTGCTCCA 33 310 665862  913  928  9953  9968 GTCTGGCAGGAGCTGT 51 311 665878 1096 1111 10329 10344 GCGCACTTGCTCCAGG 58 312 665884 1181 1196 10414 10429 GGATGAGCCCGCGGTC 56 313 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 76  39 728593  853  868  9893  9908 GACCTCAGAGAGAAGC 10 314 728594  862  877  9902  9917 AGGCTCCAGGACCTCA  7 315 728595  902  917  9942  9957 GCTGTTCGCCTGCAGG 59 316 728596  904  919  9944  9959 GAGCTGTTCGCCTGCA 14 317 728597  906  921  9946  9961 AGGAGCTGTTCGCCTG  4 318 728598  908  923  9948  9963 GCAGGAGCTGTTCGCC 44 319 728599  909  924  9949  9964 GGCAGGAGCTGTTCGC 30 320 728600  910  925  9950  9965 TGGCAGGAGCTGTTCG 15 321 728601  911  926  9951  9966 CTGGCAGGAGCTGTTC 34 322 728602  912  927  9952  9967 TCTGGCAGGAGCTGTT 33 323 728603  914  929  9954  9969 GGTCTGGCAGGAGCTG 49 324 728604  915  930  9955  9970 AGGTCTGGCAGGAGCT 60 325 728605  916  931  9956  9971 CAGGTCTGGCAGGAGC 53 326 728606  918  933  9958  9973 AGCAGGTCTGGCAGGA 35 327 728607  922  937  9962  9977 GATCAGCAGGTCTGGC 17 328 728608  924  939  9964  9979 CTGATCAGCAGGTCTG 34 329 728609  926  941  9966  9981 GGCTGATCAGCAGGTC 38 330 728610  945  960 N/A N/A GTCAGAGGCAGCATGT 24 331 728611  947  962 N/A N/A CGGTCAGAGGCAGCAT 54 332 728612  949  964 N/A N/A GTCGGTCAGAGGCAGC 44 333 728613  952  967 N/A N/A CAGGTCGGTCAGAGGC 47 334 728614  954  969 N/A N/A TCCAGGTCGGTCAGAG 24 335 728615 1001 1016 10234 10249 TGATGGTGAGGGCCCG 18 336 728616 1003 1018 10236 10251 GCTGATGGTGAGGGCC 14 337 728617 1005 1020 10238 10253 TTGCTGATGGTGAGGG 37 338 728618 1024 1039 10257 10272 GAGCCGGCAGCCATGG 13 339 728619 1032 1047 10265 10280 CTGTAGAAGAGCCGGC  0 340 728620 1034 1049 10267 10282 GGCTGTAGAAGAGCCG  0 341 728621 1036 1051 10269 10284 CTGGCTGTAGAAGAGC 21 342 728622 1038 1053 10271 10286 AGCTGGCTGTAGAAGA  9 343 728623 1040 1055 10273 10288 CCAGCTGGCTGTAGAA  5 344 728624 1067 1082 10300 10315 AGAGTTCCACCTGCTC 23 345 728625 1069 1084 10302 10317 GAAGAGTTCCACCTGC 14 346 728626 1072 1087 10305 10320 GCCGAAGAGTTCCACC 22 347 728627 1074 1089 10307 10322 GGGCCGAAGAGTTCCA 13 348 728628 1091 1106 10324 10339 CTTGCTCCAGGCTTAT 24 349 728629 1093 1108 10326 10341 CACTTGCTCCAGGCTT 46 350 728630 1094 1109 10327 10342 GCACTTGCTCCAGGCT 66 351 728631 1095 1110 10328 10343 CGCACTTGCTCCAGGC 62 352 728632 1097 1112 10330 10345 AGCGCACTTGCTCCAG 55 353 728633 1099 1114 10332 10347 GAAGCGCACTTGCTCC 43 354 728634 1100 1115 10333 10348 GGAAGCGCACTTGCTC 57 355 728635 1101 1116 10334 10349 GGGAAGCGCACTTGCT 59 356 728636 1117 1132 10350 10365 GATGTCCTCAGGGCTG 22 357 728637 1134 1149 10367 10382 CGCTGCTTGTCACTGG 67 358 728638 1161 1176 10394 10409 ACATCCAGCAGCTGGT  0 359 728639 1163 1178 10396 10411 GGACATCCAGCAGCTG  8 360 728640 1170 1185 10403 10418 CGGTCCAGGACATCCA 32 361 728641 1172 1187 10405 10420 CGCGGTCCAGGACATC 47 362 728642 1174 1189 10407 10422 CCCGCGGTCCAGGACA 11 363 728643 1176 1191 10409 10424 AGCCCGCGGTCCAGGA 20 364 728644 1177 1192 10410 10425 GAGCCCGCGGTCCAGG 48 365 728645 1179 1194 10412 10427 ATGAGCCCGCGGTCCA 44 366 728646 1180 1195 10413 10428 GATGAGCCCGCGGTCC 59 367 728647 1182 1197 10415 10430 AGGATGAGCCCGCGGT 49 368 728648 1183 1198 10416 10431 GAGGATGAGCCCGCGG 36 369 728649 1184 1199 10417 10432 GGAGGATGAGCCCGCG 14 370 728650 1185 1200 10418 10433 TGGAGGATGAGCCCGC 27 371 728651 1186 1201 10419 10434 CTGGAGGATGAGCCCG 17 372 728652 1188 1203 10421 10436 AGCTGGAGGATGAGCC  0 373 728653 1190 1205 10423 10438 GTAGCTGGAGGATGAG 13 374 728654 1192 1207 10425 10440 CTGTAGCTGGAGGATG  3 375 728655 1194 1209 10427 10442 CCCTGTAGCTGGAGGA  4 376 728656 1196 1211 10429 10444 GGCCCTGTAGCTGGAG 24 377 728657 1198 1213 10431 10446 CTGGCCCTGTAGCTGG  9 378 728658 1201 1216 10434 10449 GTCCTGGCCCTGTAGC 25 379 728659 1203 1218 10436 10451 AGGTCCTGGCCCTGTA 43 380 728660 1205 1220 10438 10453 AAAGGTCCTGGCCCTG 23 381 728661 1207 1222 10440 10455 ATAAAGGTCCTGGCCC 10 382 728662 1209 1224 10442 10457 GCATAAAGGTCCTGGC 31 383 728663 1211 1226 10444 10459 TGGCATAAAGGTCCTG 46 384 728664 1213 1228 10446 10461 GATGGCATAAAGGTCC 42 385 728665 1215 1230 10448 10463 CGGATGGCATAAAGGT 39 386

TABLE 6 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 665892 1227 1242 10460 10475 CACTGACACAGGCGGA 68 387 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 65  39 665894 1229 1244 10462 10477 TGCACTGACACAGGCG 42 388 665895 1242 1257 10475 10490 CTCCAGAACACCTTGC 44 389 665900 1272 1287 10505 10520 CATGAGTCATGGGCTG 54 390 665902 1301 1316 10534 10549 TCTTGACCTCCCGCTG 37 391 665903 1309 1324 10542 10557 AAGCTTGGTCTTGACC 49 392 665908 1363 1378 10684 10699 GGTCTGGCCCTTTTGG 66 393 728666 1217 1232 10450 10465 GGCGGATGGCATAAAG 32 394 728667 1223 1238 10456 10471 GACACAGGCGGATGGC 49 395 728668 1224 1239 10457 10472 TGACACAGGCGGATGG 27 396 728669 1226 1241 10459 10474 ACTGACACAGGCGGAT 51 397 728670 1230 1245 10463 10478 TTGCACTGACACAGGC 68 398 728671 1231 1246 10464 10479 CTTGCACTGACACAGG 42 399 728672 1232 1247 10465 10480 CCTTGCACTGACACAG 56 400 728673 1233 1248 10466 10481 ACCTTGCACTGACACA 60 401 728674 1234 1249 10467 10482 CACCTTGCACTGACAC 57 402 728675 1237 1252 10470 10485 GAACACCTTGCACTGA 34 403 728676 1238 1253 10471 10486 AGAACACCTTGCACTG 39 404 728677 1239 1254 10472 10487 CAGAACACCTTGCACT 25 405 728678 1240 1255 10473 10488 CCAGAACACCTTGCAC 30 406 728679 1241 1256 10474 10489 TCCAGAACACCTTGCA 39 407 728680 1243 1258 10476 10491 GCTCCAGAACACCTTG 39 408 728681 1244 1259 10477 10492 CGCTCCAGAACACCTT 59 409 728682 1245 1260 10478 10493 CCGCTCCAGAACACCT 37 410 728683 1246 1261 10479 10494 CCCGCTCCAGAACACC 41 411 728684 1247 1262 10480 10495 GCCCGCTCCAGAACAC 19 412 728685 1249 1264 10482 10497 AGGCCCGCTCCAGAAC 24 413 728686 1251 1266 10484 10499 CAAGGCCCGCTCCAGA 28 414 728687 1253 1268 10486 10501 CACAAGGCCCGCTCCA 16 415 728688 1255 1270 10488 10503 GGCACAAGGCCCGCTC 12 416 728689 1257 1272 10490 10505 GAGGCACAAGGCCCGC 17 417 728690 1259 1274 10492 10507 CTGAGGCACAAGGCCC 13 418 728691 1264 1279 10497 10512 ATGGGCTGAGGCACAA 42 419 728692 1267 1282 10500 10515 GTCATGGGCTGAGGCA 51 420 728693 1268 1283 10501 10516 AGTCATGGGCTGAGGC 52 421 728694 1269 1284 10502 10517 GAGTCATGGGCTGAGG 59 422 728695 1270 1285 10503 10518 TGAGTCATGGGCTGAG 67 423 728696 1271 1286 10504 10519 ATGAGTCATGGGCTGA 75 424 728697 1273 1288 10506 10521 GCATGAGTCATGGGCT 23 425 728698 1274 1289 10507 10522 GGCATGAGTCATGGGC 47 426 728699 1296 1311 10529 10544 ACCTCCCGCTGGATGG 45 427 728700 1297 1312 10530 10545 GACCTCCCGCTGGATG 38 428 728701 1298 1313 10531 10546 TGACCTCCCGCTGGAT 53 429 728702 1299 1314 10532 10547 TTGACCTCCCGCTGGA 38 430 728703 1300 1315 10533 10548 CTTGACCTCCCGCTGG 33 431 728704 1302 1317 10535 10550 GTCTTGACCTCCCGCT 56 432 728705 1303 1318 10536 10551 GGTCTTGACCTCCCGC 71 433 728706 1306 1321 10539 10554 CTTGGTCTTGACCTCC 73 434 728707 1307 1322 10540 10555 GCTTGGTCTTGACCTC 79 435 728708 1308 1323 10541 10556 AGCTTGGTCTTGACCT 79 436 728709 1310 1325 10543 10558 AAAGCTTGGTCTTGAC 46 437 728710 1311 1326 10544 10559 AAAAGCTTGGTCTTGA 29 438 728711 1312 1327 10545 10560 GAAAAGCTTGGTCTTG 24 439 728712 1313 1328 10546 10561 TGAAAAGCTTGGTCTT 11 440 728713 1314 1329 10547 10562 CTGAAAAGCTTGGTCT 13 441 728714 1316 1331 10549 10564 GGCTGAAAAGCTTGGT 11 442 728715 1318 1333 10551 10566 CAGGCTGAAAAGCTTG  1 443 728716 1320 1335 10553 10568 TCCAGGCTGAAAAGCT  5 444 728717 1340 1355 N/A N/A TGAGCTCATTGAGAAA 10 445 728718 1342 1357 N/A N/A GATGAGCTCATTGAGA 33 446 728719 1344 1359 N/A N/A AGGATGAGCTCATTGA 55 447 728720 1346 1361 N/A N/A ACAGGATGAGCTCATT 41 448 728721 1348 1363 N/A N/A GAACAGGATGAGCTCA 45 449 728722 1350 1365 10671 10686 TGGAACAGGATGAGCT 47 450 728723 1358 1373 10679 10694 GGCCCTTTTGGAACAG 29 451 728724 1359 1374 10680 10695 TGGCCCTTTTGGAACA 34 452 728725 1360 1375 10681 10696 CTGGCCCTTTTGGAAC 20 453 728726 1361 1376 10682 10697 TCTGGCCCTTTTGGAA 14 454 728727 1362 1377 10683 10698 GTCTGGCCCTTTTGGA 33 455 728728 1364 1379 10685 10700 TGGTCTGGCCCTTTTG 56 456 728729 1365 1380 10686 10701 TTGGTCTGGCCCTTTT 54 457 728730 1366 1381 10687 10702 GTTGGTCTGGCCCTTT 53 458 728731 1367 1382 10688 10703 TGTTGGTCTGGCCCTT 50 459 728732 1368 1383 10689 10704 GTGTTGGTCTGGCCCT 47 460 728733 1386 1401 10707 10722 ATCTCGAAGGGTGGTG 40 461 728734 1389 1404 10710 10725 AAGATCTCGAAGGGTG 52 462 728735 1392 1407 10713 10728 AAGAAGATCTCGAAGG 28 463

TABLE 7 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 IRF5 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) bition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 73  39 665925 1506 1521 11071 11086 GATAGCTCCCCTGAGA 29 464 665926 1512 1527 11077 11092 GACCAAGATAGCTCCC 50 465 665929 1530 1545 11095 11110 AGCCGGATACTATCAG 49 466 665930 1536 1551 11101 11116 ATCTGTAGCCGGATAC 39 467 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 62 468 728736 1394 1409 10715 10730 AGAAGAAGATCTCGAA 13 469 728737 1396 1411 10717 10732 GCAGAAGAAGATCTCG 45 470 728738 1419 1434 10740 10755 CGGTCAGGCCATTCTT 52 471 728739 1421 1436 10742 10757 TGCGGTCAGGCCATTC 68 472 728740 1423 1438 10744 10759 TTTGCGGTCAGGCCAT 37 473 728741 1426 1441 10747 10762 GGGTTTGCGGTCAGGC 71 474 728742 1441 1456 10762 10777 GAGCTTCTTCTCTCGG 22 475 728743 1443 1458 10764 10779 ATGAGCTTCTTCTCTC  0 476 728744 1445 1460 10766 10781 TAATGAGCTTCTTCTC 14 477 728745 1447 1462 10768 10783 AGTAATGAGCTTCTTC 36 478 728746 1449 1464 10770 10785 ACAGTAATGAGCTTCT 30 479 728747 1451 1466 10772 10787 GTACAGTAATGAGCTT 26 480 728748 1453 1468 10774 10789 CTGTACAGTAATGAGC 37 481 728749 1455 1470 10776 10791 ACCTGTACAGTAATGA 28 482 728750 1457 1472 N/A N/A CCACCTGTACAGTAAT 27 483 728751 1459 1474 N/A N/A CACCACCTGTACAGTA 42 484 728752 1461 1476 N/A N/A GGCACCACCTGTACAG 27 485 728753 1463 1478 N/A N/A CAGGCACCACCTGTAC 53 486 728754 1465 1480 N/A N/A TACAGGCACCACCTGT  0 487 728755 1467 1482 11032 11047 GCTACAGGCACCACCT 37 488 728756 1469 1484 11034 11049 CTGCTACAGGCACCAC 53 489 728757 1471 1486 11036 11051 AGCTGCTACAGGCACC 41 490 728758 1473 1488 11038 11053 CGAGCTGCTACAGGCA 54 491 728759 1475 1490 11040 11055 GTCGAGCTGCTACAGG 63 492 728760 1477 1492 11042 11057 CAGTCGAGCTGCTACA 34 493 728761 1479 1494 11044 11059 AGCAGTCGAGCTGCTA  3 494 728762 1481 1496 11046 11061 GCAGCAGTCGAGCTGC 13 495 728763 1483 1498 11048 11063 CAGCAGCAGTCGAGCT 16 496 728764 1485 1500 11050 11065 TCCAGCAGCAGTCGAG 23 497 728765 1487 1502 11052 11067 TCTCCAGCAGCAGTCG 30 498 728766 1489 1504 11054 11069 CATCTCCAGCAGCAGT 31 499 728767 1492 1507 11057 11072 GAACATCTCCAGCAGC 47 500 728768 1495 1510 11060 11075 TGAGAACATCTCCAGC 33 501 728769 1497 1512 11062 11077 CCTGAGAACATCTCCA 60 502 728770 1499 1514 11064 11079 CCCCTGAGAACATCTC 43 503 728771 1501 1516 11066 11081 CTCCCCTGAGAACATC 42 504 728772 1502 1517 11067 11082 GCTCCCCTGAGAACAT 55 505 728773 1503 1518 11068 11083 AGCTCCCCTGAGAACA 54 506 728774 1504 1519 11069 11084 TAGCTCCCCTGAGAAC 29 507 728775 1505 1520 11070 11085 ATAGCTCCCCTGAGAA 15 508 728776 1507 1522 11072 11087 AGATAGCTCCCCTGAG 42 509 728777 1508 1523 11073 11088 AAGATAGCTCCCCTGA 52 510 728778 1509 1524 11074 11089 CAAGATAGCTCCCCTG 64 511 728779 1510 1525 11075 11090 CCAAGATAGCTCCCCT 50 512 728780 1511 1526 11076 11091 ACCAAGATAGCTCCCC 21 513 728781 1513 1528 11078 11093 TGACCAAGATAGCTCC 43 514 728782 1514 1529 11079 11094 CTGACCAAGATAGCTC 51 515 728783 1515 1530 11080 11095 GCTGACCAAGATAGCT 23 516 728784 1516 1531 11081 11096 AGCTGACCAAGATAGC 31 517 728785 1517 1532 11082 11097 CAGCTGACCAAGATAG 34 518 728786 1519 1534 11084 11099 ATCAGCTGACCAAGAT 28 519 728787 1521 1536 11086 11101 CTATCAGCTGACCAAG 48 520 728788 1523 1538 11088 11103 TACTATCAGCTGACCA 49 521 728789 1525 1540 11090 11105 GATACTATCAGCTGAC 58 522 728790 1526 1541 11091 11106 GGATACTATCAGCTGA 51 523 728791 1527 1542 11092 11107 CGGATACTATCAGCTG 55 524 728792 1528 1543 11093 11108 CCGGATACTATCAGCT 41 525 728793 1529 1544 11094 11109 GCCGGATACTATCAGC 68 526 728794 1531 1546 11096 11111 TAGCCGGATACTATCA 40 527 728795 1532 1547 11097 11112 GTAGCCGGATACTATC 48 528 728796 1533 1548 11098 11113 TGTAGCCGGATACTAT 34 529 728797 1534 1549 11099 11114 CTGTAGCCGGATACTA 52 530 728798 1535 1550 11100 11115 TCTGTAGCCGGATACT 53 531 728799 1537 1552 11102 11117 GATCTGTAGCCGGATA 46 532 728800 1538 1553 11103 11118 AGATCTGTAGCCGGAT 67 533 728801 1543 1558 11108 11123 GTTTGAGATCTGTAGC 55 534 728802 1556 1571 11121 11136 CTTTGAGGTCTGGGTT 63 535 728803 1557 1572 11122 11137 TCTTTGAGGTCTGGGT 55 536 728804 1558 1573 11123 11138 GTCTTTGAGGTCTGGG 61 537 728805 1559 1574 11124 11139 GGTCTTTGAGGTCTGG 58 538 728806 1560 1575 11125 11140 CGGTCTTTGAGGTCTG 74 539 728807 1562 1577 11127 11142 TGCGGTCTTTGAGGTC 58 540

TABLE 8 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 72 39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 62 468 665942 1613 1628 11178 11193 ACCGCTGCTGGGACTG 40 541 728808 1563 1578 11128 11143 ATGCGGTCTTTGAGGT 37 542 728809 1564 1579 11129 11144 CATGCGGTCTTTGAGG 17 543 728810 1565 1580 11130 11145 CCATGCGGTCTTTGAG 43 544 728811 1566 1581 11131 11146 ACCATGCGGTCTTTGA 26 545 728812 1568 1583 11133 11148 CCACCATGCGGTCTTT 9 546 728813 1570 1585 11135 11150 CTCCACCATGCGGTCT 22 547 728814 1572 1587 11137 11152 TGCTCCACCATGCGGT 23 548 728815 1574 1589 11139 11154 ATTGCTCCACCATGCG 0 549 728816 1576 1591 11141 11156 GAATTGCTCCACCATG 0 550 728817 1578 1593 11143 11158 TTGAATTGCTCCACCA 0 551 728818 1580 1595 11145 11160 CCTTGAATTGCTCCAC 0 552 728819 1582 1597 11147 11162 CTCCTTGAATTGCTCC 0 553 728820 1584 1599 11149 11164 AGCTCCTTGAATTGCT 0 554 728821 1586 1601 11151 11166 GGAGCTCCTTGAATTG 0 555 728822 1588 1603 11153 11168 ATGGAGCTCCTTGAAT 2 556 728823 1590 1605 11155 11170 TGATGGAGCTCCTTGA 0 557 728824 1592 1607 11157 11172 TGTGATGGAGCTCCTT 0 558 728825 1594 1609 11159 11174 GATGTGATGGAGCTCC 30 559 728826 1596 1611 11161 11176 CAGATGTGATGGAGCT 27 560 728827 1600 1615 11165 11180 CTGCCAGATGTGATGG 7 561 728828 1602 1617 11167 11182 GACTGCCAGATGTGAT 0 562 728829 1604 1619 11169 11184 GGGACTGCCAGATGTG 31 563 728830 1606 1621 11171 11186 CTGGGACTGCCAGATG 40 564 728831 1608 1623 11173 11188 TGCTGGGACTGCCAGA 24 565 728832 1609 1624 11174 11189 CTGCTGGGACTGCCAG 19 566 728833 1610 1625 11175 11190 GCTGCTGGGACTGCCA 24 567 728834 1612 1627 11177 11192 CCGCTGCTGGGACTGC 37 568 728835 1614 1629 11179 11194 AACCGCTGCTGGGACT 19 569 728836 1616 1631 11181 11196 GCAACCGCTGCTGGGA 38 570 728837 1618 1633 11183 11198 CTGCAACCGCTGCTGG 26 571 728838 1620 1635 11185 11200 GGCTGCAACCGCTGCT 2 572 728839 1624 1639 11189 11204 CACAGGCTGCAACCGC 26 573 728840 1626 1641 11191 11206 GCCACAGGCTGCAACC 21 574 728841 1628 1643 11193 11208 GGGCCACAGGCTGCAA 37 575 728842 1650 1665 11215 11230 AGGCCTGCTCCAGGAG 0 576 728843 1654 1669 11219 11234 ACCAAGGCCTGCTCCA 30 577 728844 1656 1671 11221 11236 ACACCAAGGCCTGCTC 41 578 728845 1659 1674 11224 11239 CCAACACCAAGGCCTG 8 579 728846 1661 1676 11226 11241 GGCCAACACCAAGGCC 0 580 728847 1663 1678 11228 11243 CTGGCCAACACCAAGG 18 581 728848 1666 1681 11231 11246 CCCCTGGCCAACACCA 0 582 728849 1668 1683 11233 11248 GGCCCCTGGCCAACAC 0 583 728850 1670 1685 11235 11250 AGGGCCCCTGGCCAAC 21 584 728851 1676 1691 11241 11256 TAGGCCAGGGCCCCTG 0 585 728852 1678 1693 11243 11258 CATAGGCCAGGGCCCC 0 586 728853 1680 1695 11245 11260 TGCATAGGCCAGGGCC 0 587 728854 1682 1697 11247 11262 GGTGCATAGGCCAGGG 0 588 728855 1684 1699 11249 11264 TGGGTGCATAGGCCAG 0 589 728856 1687 1702 11252 11267 AGCTGGGTGCATAGGC 0 590 728857 1690 1705 11255 11270 GCCAGCTGGGTGCATA 15 591 728858 1693 1708 11258 11273 CATGCCAGCTGGGTGC 28 592 728859 1695 1710 11260 11275 TGCATGCCAGCTGGGT 32 593 728860 1697 1712 11262 11277 ATTGCATGCCAGCTGG 34 594 728861 1699 1714 11264 11279 TTATTGCATGCCAGCT 19 595 728862 1701 1716 11266 11281 TGTTATTGCATGCCAG 35 596 728863 1703 1718 11268 11283 CTTGTTATTGCATGCC 51 597 728864 1705 1720 11270 11285 GCCTTGTTATTGCATG 16 598 728865 1707 1722 11272 11287 CAGCCTTGTTATTGCA 3 599 728866 1709 1724 11274 11289 TGCAGCCTTGTTATTG 0 600 728867 1711 1726 11276 11291 TCTGCAGCCTTGTTAT 0 601 728868 1713 1728 11278 11293 CGTCTGCAGCCTTGTT 43 602 728869 1715 1730 11280 11295 ACCGTCTGCAGCCTTG 51 603 728870 1717 1732 11282 11297 TCACCGTCTGCAGCCT 14 604 728871 1719 1734 11284 11299 AGTCACCGTCTGCAGC 36 605 728872 1721 1736 11286 11301 CCAGTCACCGTCTGCA 57 606 728873 1723 1738 11288 11303 GGCCAGTCACCGTCTG 6 607 728874 1725 1740 11290 11305 AGGGCCAGTCACCGTC 28 608 728875 1727 1742 11292 11307 CCAGGGCCAGTCACCG 30 609 728876 1731 1746 11296 11311 GAAGCCAGGGCCAGTC 30 610 728877 1742 1757 11307 11322 CCGCCACCCAGGAAGC 30 611 728878 1744 1759 11309 11324 CACCGCCACCCAGGAA 9 612 728879 1746 1761 11311 11326 CGCACCGCCACCCAGG 46 613 728880 1748 1763 11313 11328 TCCGCACCGCCACCCA 29 614 728881 1749 1764 11314 11329 GTCCGCACCGCCACCC 30 615 728882 1750 1765 11315 11330 AGTCCGCACCGCCACC 27 616 728883 1751 1766 11316 11331 CAGTCCGCACCGCCAC 56 617

TABLE 9 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 74  39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 60 468 665962 1753 1768 11318 11333 ATCAGTCCGCACCGCC 53 618 665964 1765 1780 11330 11345 TCACATCTCCACATCA 36 619 665973 1903 1918 11468 11483 AGACCAGAGACAGCCC 30 620 665975 1911 1926 11476 11491 GGCTGACCAGACCAGA 40 621 665981 1951 1966 11516 11531 GAGTTCTTTCCCTGCT 41 622 728884 1752 1767 11317 11332 TCAGTCCGCACCGCCA 46 623 728885 1754 1769 11319 11334 CATCAGTCCGCACCGC 23 624 728886 1755 1770 11320 11335 ACATCAGTCCGCACCG 48 625 728887 1756 1771 11321 11336 CACATCAGTCCGCACC 57 626 728888 1757 1772 11322 11337 CCACATCAGTCCGCAC 37 627 728889 1758 1773 11323 11338 TCCACATCAGTCCGCA 24 628 728890 1760 1775 11325 11340 TCTCCACATCAGTCCG 33 629 728891 1761 1776 11326 11341 ATCTCCACATCAGTCC 56 630 728892 1762 1777 11327 11342 CATCTCCACATCAGTC 37 631 728893 1763 1778 11328 11343 ACATCTCCACATCAGT 56 632 728894 1764 1779 11329 11344 CACATCTCCACATCAG 65 633 728895 1766 1781 11331 11346 GTCACATCTCCACATC 47 634 728896 1767 1782 11332 11347 TGTCACATCTCCACAT 21 635 728897 1768 1783 11333 11348 CTGTCACATCTCCACA 46 636 728898 1769 1784 11334 11349 GCTGTCACATCTCCAC 73 637 728899 1770 1785 11335 11350 GGCTGTCACATCTCCA 64 638 728900 1786 1801 11351 11366 GCCAGGTGCTCATCGG 37 639 728901 1788 1803 11353 11368 CAGCCAGGTGCTCATC 37 640 728902 1790 1805 11355 11370 GCCAGCCAGGTGCTCA 42 641 728903 1803 1818 11368 11383 GTAGGACCCTGCAGCC 31 642 728904 1805 1820 11370 11385 AGGTAGGACCCTGCAG 6 643 728905 1807 1822 11372 11387 AGAGGTAGGACCCTGC 60 644 728906 1810 1825 11375 11390 CCCAGAGGTAGGACCC 42 645 728907 1812 1827 11377 11392 AACCCAGAGGTAGGAC 32 646 728908 1814 1829 11379 11394 GAAACCCAGAGGTAGG 44 647 728909 1825 1840 11390 11405 TCCACTTCCAGGAAAC 25 648 728910 1833 1848 11398 11413 GGCCCAAATCCACTTC 11 649 728911 1835 1850 11400 11415 TTGGCCCAAATCCACT 9 650 728912 1837 1852 11402 11417 TCTTGGCCCAAATCCA 22 651 728913 1839 1854 11404 11419 CTTCTTGGCCCAAATC 15 652 728914 1841 1856 11406 11421 TCCTTCTTGGCCCAAA 31 653 728915 1859 1874 11424 11439 CTCGGGCCTTTCTCCC 2 654 728916 1861 1876 11426 11441 GGCTCGGGCCTTTCTC 10 655 728917 1884 1899 11449 11464 AGAGAAAGGCCCGGGA 0 656 728918 1886 1901 11451 11466 GGAGAGAAAGGCCCGG 0 657 728919 1898 1913 11463 11478 AGAGACAGCCCAGGAG 13 658 728920 1901 1916 11466 11481 ACCAGAGACAGCCCAG 52 659 728921 1902 1917 11467 11482 GACCAGAGACAGCCCA 42 660 728922 1904 1919 11469 11484 CAGACCAGAGACAGCC 38 661 728923 1905 1920 11470 11485 CCAGACCAGAGACAGC 17 662 728924 1906 1921 11471 11486 ACCAGACCAGAGACAG 30 663 728925 1907 1922 11472 11487 GACCAGACCAGAGACA 14 664 728926 1908 1923 11473 11488 TGACCAGACCAGAGAC 7 665 728927 1910 1925 11475 11490 GCTGACCAGACCAGAG 26 666 728928 1912 1927 11477 11492 AGGCTGACCAGACCAG 14 667 728929 1916 1931 11481 11496 AGCCAGGCTGACCAGA 13 668 728930 1919 1934 11484 11499 GAGAGCCAGGCTGACC 26 669 728931 1923 1938 11488 11503 TCCCGAGAGCCAGGCT 26 670 728932 1925 1940 11490 11505 TTTCCCGAGAGCCAGG 26 671 728933 1928 1943 11493 11508 GAATTTCCCGAGAGCC 34 672 728934 1930 1945 11495 11510 CTGAATTTCCCGAGAG 33 673 728935 1932 1947 11497 11512 GGCTGAATTTCCCGAG 39 674 728936 1934 1949 11499 11514 ATGGCTGAATTTCCCG 39 675 728937 1936 1951 11501 11516 TCATGGCTGAATTTCC 36 676 728938 1938 1953 11503 11518 GCTCATGGCTGAATTT 30 677 728939 1940 1955 11505 11520 CTGCTCATGGCTGAAT 40 678 728940 1942 1957 11507 11522 CCCTGCTCATGGCTGA 51 679 728941 1946 1961 11511 11526 CTTTCCCTGCTCATGG 45 680 728942 1947 1962 11512 11527 TCTTTCCCTGCTCATG 54 681 728943 1948 1963 11513 11528 TTCTTTCCCTGCTCAT 16 682 728944 1949 1964 11514 11529 GTTCTTTCCCTGCTCA 56 683 728945 1950 1965 11515 11530 AGTTCTTTCCCTGCTC 56 684 728946 1952 1967 11517 11532 AGAGTTCTTTCCCTGC 56 685 728947 1953 1968 11518 11533 GAGAGTTCTTTCCCTG 54 686 728948 1954 1969 11519 11534 GGAGAGTTCTTTCCCT 32 687 728949 1955 1970 11520 11535 GGGAGAGTTCTTTCCC 1 688 728950 1956 1971 11521 11536 TGGGAGAGTTCTTTCC 24 689 728951 1958 1973 11523 11538 GTTGGGAGAGTTCTTT 29 690 728952 1970 1985 11535 11550 CTAGGCCCCAGGGTTG 35 691 728953 1972 1987 11537 11552 AGCTAGGCCCCAGGGT 23 692 728954 1974 1989 11539 11554 ACAGCTAGGCCCCAGG 64 693 728955 1976 1991 11541 11556 ATACAGCTAGGCCCCA 14 694

TABLE 10 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 73  39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 69 468 666013 2215 2230 11780 11795 GTTCTTGGACTCTCAA 65 695 666015 2228 2243 11793 11808 ATTTCTGCTCCAGGTT 54 696 729028 2190 2205 11755 11770 AGCTGCCAGCCTTGAG 50 697 729029 2191 2206 11756 11771 TAGCTGCCAGCCTTGA 57 698 729030 2192 2207 11757 11772 GTAGCTGCCAGCCTTG 65 699 729031 2194 2209 11759 11774 GGGTAGCTGCCAGCCT 41 700 729032 2210 2225 11775 11790 TGGACTCTCAAGAAGG 55 701 729033 2211 2226 11776 11791 TTGGACTCTCAAGAAG 37 702 729034 2212 2227 11777 11792 CTTGGACTCTCAAGAA 38 703 729035 2213 2228 11778 11793 TCTTGGACTCTCAAGA 0 704 729036 2214 2229 11779 11794 TTCTTGGACTCTCAAG 55 705 729037 2216 2231 11781 11796 GGTTCTTGGACTCTCA 80 706 729038 2217 2232 11782 11797 AGGTTCTTGGACTCTC 85 707 729039 2218 2233 11783 11798 CAGGTTCTTGGACTCT 74 708 729040 2219 2234 11784 11799 CCAGGTTCTTGGACTC 67 709 729041 2220 2235 11785 11800 TCCAGGTTCTTGGACT 39 710 729042 2222 2237 11787 11802 GCTCCAGGTTCTTGGA 11 711 729043 2223 2238 11788 11803 TGCTCCAGGTTCTTGG 44 712 729044 2224 2239 11789 11804 CTGCTCCAGGTTCTTG 62 713 729045 2225 2240 11790 11805 TCTGCTCCAGGTTCTT 60 714 729046 2226 2241 11791 11806 TTCTGCTCCAGGTTCT 54 715 729047 2227 2242 11792 11807 TTTCTGCTCCAGGTTC 63 716 729048 2229 2244 11794 11809 TATTTCTGCTCCAGGT 63 717 729049 2230 2245 11795 11810 TTATTTCTGCTCCAGG 76 718 729050 2231 2246 11796 11811 ATTATTTCTGCTCCAG 76 719 729051 2232 2247 11797 11812 AATTATTTCTGCTCCA 58 720 729052 2260 2275 11825 11840 AACATTCATTAATCCA 55 721 729053 2278 2293 11843 11858 ACAGCTGAGTCTGTTT 26 722 729055 2300 2315 11865 11880 TGGTAGTAGTAAAAGG 24 723 729060 2310 2325 11875 11890 TGGGAGCAACTGGTAG 33 724 729064 2322 2337 11887 11902 GGTGGAGCAGCATGGG 14 725 729067 2336 2351 11901 11916 CCGAAACAGGGCCTGG 33 726 729072 2346 2361 11911 11926 CAGTTGGCATCCGAAA 8 727 729077 2385 2400 11950 11965 AATGGTCGCAAGCTGG 26 728 729082 2395 2410 11960 11975 TCCCAGTGCCAATGGT 5 729 729086 2417 2432 11982 11997 CATCAGCCCAGAAGCC 12 730 729090 2427 2442 11992 12007 CCAACTGACCCATCAG 8 731 729095 2437 2452 12002 12017 TTATGAAGGCCCAACT 0 732 729100 2447 2462 12012 12027 AGGTGAGTGTTTATGA 33 733 729105 2457 2472 12022 12037 AAAGCCAGCCAGGTGA 30 734 729106 2486 2501 12051 12066 TTGCTTCAGCCAGCTT 15 735 729110 2496 2511 12061 12076 TTCCACACCCTTGCTT 11 736 729112 2515 2530 12080 12095 ACTGTGCACACATTTA 53 737 729116 2525 2540 12090 12105 AGTTTTCCAGACTGTG 28 738 729120 2536 2551 12101 12116 CTGATTCTGACAGTTT 0 739 729123 2547 2562 12112 12127 TTATGGGAAAACTGAT 0 740 729125 2557 2572 12122 12137 GCCCACCCTTTTATGG 0 741 729129 2567 2582 12132 12147 TGCAATGCTAGCCCAC 54 742 729134 2577 2592 12142 12157 CAAATGCAGCTGCAAT 27 743 729139 2588 2603 12153 12168 TTGAATGGTCCCAAAT 22 744 729144 2599 2614 12164 12179 GAGTGACAGATTTGAA 55 745 729146 2620 2635 12185 12200 AGCACAGGAATATACA 36 746 729150 2637 2652 12202 12217 GCCCTGATATATTTAA 0 747 729155 2647 2662 12212 12227 TACATGCACTGCCCTG 31 748 729160 2657 2672 12222 12237 CAGGATGATTTACATG 5 749 729164 2703 2718 12268 12283 ACTGTCCCCACCTCGG 10 750 729165 2720 2735 12285 12300 ACTAAGAGAACTCACT 31 751 729167 2747 2762 12312 12327 GGCTCTTTAACAACCA 20 752 729170 2761 2776 12326 12341 GCGGGTAGGTGCCAGG 40 753 729175 2771 2786 12336 12351 TGAAGTGAGAGCGGGT 45 754 729180 2789 2804 12354 12369 GTGCAGAGATGACACA 0 755 729182 2800 2815 12365 12380 TGGGCTGGAGTGTGCA 30 756 729185 2820 2835 12385 12400 CAATGGCTGAAGGCAG 14 757 729190 2876 2891 12441 12456 GCTGGGCATCAAGATT 7 758 729194 2885 2900 12450 12465 GTTCTGATGGCTGGGC 50 759 729251 N/A N/A 176 191 CTGGAATGGCAAAACT 12 760 729252 N/A N/A 197 212 GCCACTGGCTCTTTTG 0 761 729253 N/A N/A 207 222 CCCTAGACTGGCCACT 1 762 729254 N/A N/A 218 233 ACGGCGCGGTGCCCTA 10 763 729255 N/A N/A 257 272 AGCCTCGGGCCAGGCC 12 764 729256 N/A N/A 267 282 ATCCGGGCTGAGCCTC 8 765 729257 N/A N/A 292 307 CCCCGCACTGACCTGG 43 766 729258 N/A N/A 302 317 CCACTCCGGGCCCCGC 0 767 729259 N/A N/A 312 327 CCCCGCGAATCCACTC 0 768 729260 N/A N/A 364 379 CGCCCCTGGGCAGCTG 0 769 729635 N/A N/A 228 243 GAGATGCCAGACGGCG 0 770 729636 N/A N/A 344 359 TGAGCTCCGGGCGCGG 5 771

TABLE 11 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 74  39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 57 468 729261 N/A N/A 502 517 GACCCACCTGTCTGCG 7 772 729262 N/A N/A 512 527 CGGCGGCCGGGACCCA 18 773 729263 N/A N/A 532 547 CGGACGCAGAGAGGAG 20 774 729264 N/A N/A 561 576 CTCCCGCCACCCTCGG 9 775 729265 N/A N/A 571 586 GCCGGCACCGCTCCCG 0 776 729266 N/A N/A 594 609 TAGGCCTAGACTTGGG 26 777 729267 N/A N/A 635 650 TCCCGCCGCCCGCAGG 10 778 729268 N/A N/A 645 660 CCAGTCTTCATCCCGC 33 779 729269 N/A N/A 656 671 CCCGCCCTACTCCAGT 26 780 729270 N/A N/A 686 701 CTCGCTTTCCAGGCGC 4 781 729271 N/A N/A 696 711 CCCCCCCGAGCTCGCT 8 782 729272 N/A N/A 706 721 GCTGTAGGCACCCCCC 19 783 729273 N/A N/A 736 751 TGGAAGTCCCAGGCCG 21 784 729274 N/A N/A 767 782 CCCCAAACCGATCGGG 0 785 729275 N/A N/A 801 816 CCGCCTGGGTCACTGG 11 786 729276 N/A N/A 811 826 GCCCACTCCGCCGCCT 0 787 729277 N/A N/A 866 881 CTGGGCGATGGCGAGG 10 788 729278 N/A N/A 876 891 AACCCCCATTCTGGGC 6 789 729279 N/A N/A 886 901 GGCTCCCGGGAACCCC 11 790 729280 N/A N/A 911 926 TGTGGTCCAAGCCAGC 29 791 729281 N/A N/A 931 946 AGGATCGGGCCTCGCT 30 792 729282 N/A N/A 941 956 ATCGAAAGTAAGGATC 17 793 729283 N/A N/A 957 972 GAGCAAGGGCGAGTGC 29 794 729284 N/A N/A 967 982 GGCCCGGTAAGAGCAA 6 795 729285 N/A N/A 986 1001 TTTCCGAAAGGGTGAG 32 796 729286 N/A N/A 1028 1043 GCCTGAAGATCCCGGG 14 797 729287 N/A N/A 1038 1053 CCTGCCATTGGCCTGA 14 798 729288 N/A N/A 1057 1072 CCCAAACTCTTGCACA 25 799 729289 N/A N/A 1074 1089 ACCTGACACCATCTTC 9 800 729290 N/A N/A 1085 1100 ACGCAGCCTCTACCTG 0 801 729291 N/A N/A 1096 1111 CGAGCCCAGGGACGCA 16 802 729292 N/A N/A 1107 1122 ATTCCCGGCCGCGAGC 19 803 729293 N/A N/A 1117 1132 AGAGTCTGCCATTCCC 44 804 729294 N/A N/A 1157 1172 GAACTATTGCGCCCCA 35 805 729295 N/A N/A 1167 1182 ACCAGCCCAGGAACTA 15 806 729296 N/A N/A 1177 1192 ACCTGAGGAAACCAGC 15 807 729297 N/A N/A 1190 1205 GTTCTGGGACAGGACC 19 808 729298 N/A N/A 1213 1228 CCTCTTCATTGTTGCC 42 809 729299 N/A N/A 1244 1259 CATGCTAGCCTCACTT 23 810 729300 N/A N/A 1268 1283 AACCATCTCCCCACGC 21 811 729301 N/A N/A 1278 1293 GTCCGGAGACAACCAT 13 812 729302 N/A N/A 1308 1323 TCCCAGGTACCCGCTC 7 813 729303 N/A N/A 1330 1345 AGTCCCCCACTCCAGC 23 814 729304 N/A N/A 1342 1357 CGAGGCTGGGAAAGTC 18 815 729305 N/A N/A 1370 1385 CCTCGCCCTGCTGTGT 18 816 729306 N/A N/A 1380 1395 GCACCCCGGTCCTCGC 27 817 729307 N/A N/A 1557 1572 ATTCTGGGCCCTCGAG 3 818 729308 N/A N/A 1579 1594 CTGGTTCTGGTCACTT 41 819 729309 N/A N/A 1591 1606 GCCGAGCCCTCTCTGG 13 820 729310 N/A N/A 1601 1616 CATCGATACAGCCGAG 42 821 729311 N/A N/A 1638 1653 CTTGCCAGAGGGCCTC 40 822 729312 N/A N/A 1676 1691 CCCCATAACTACTGGG 20 823 729313 N/A N/A 1702 1717 GAACCCCTCAGCCCCA 8 824 729314 N/A N/A 1712 1727 TTGACTCTTGGAACCC 40 825 729315 N/A N/A 1722 1737 AGTGCTTCCCTTGACT 20 826 729316 N/A N/A 1748 1763 CTTTAGATAAAAAGGG 12 827 729317 N/A N/A 1758 1773 AAAGTAGGGCCTTTAG 27 828 729318 N/A N/A 1833 1848 GCCCAGAAAGAAGCTT 5 829 729319 N/A N/A 1867 1882 GGTCCAGACAGGCTGA 15 830 729320 N/A N/A 1909 1924 CTCCGGGTCAGCTGCC 25 831 729321 N/A N/A 1919 1934 AATCCCACCCCTCCGG 8 832 729322 N/A N/A 1942 1957 CCCTGTACAGGCCCTG 1 833 729323 N/A N/A 1992 2007 ACATGTCTCCTTGCAA 6 834 729324 N/A N/A 2002 2017 GGTCTGGGTCACATGT 33 835 729325 N/A N/A 2036 2051 GCCAGACAGCAGGCGC 11 836 729326 N/A N/A 2047 2062 TAGTAAGAGTGGCCAG 16 837 729327 N/A N/A 2058 2073 CACAGCAGTCCTAGTA 9 838 729328 N/A N/A 2068 2083 GAGGAAGTGCCACAGC 17 839 729329 N/A N/A 2100 2115 TGCAATTCATGGGCAC 18 840 729330 N/A N/A 2110 2125 ACCCAGGAGCTGCAAT 4 841 729331 N/A N/A 2129 2144 AGACAGTGCCCCCACC 5 842 729332 N/A N/A 2170 2185 TAAGCCCACAGCTCAC 0 843 729333 N/A N/A 2187 2202 GACCTGCTGAGGTGGG 15 844 729637 N/A N/A 716 731 GGCGCACCCTGCTGTA 17 845 729638 N/A N/A 1234 1249 TCACTTTTCCTCCACG 38 846 729639 N/A N/A 1452 1467 GGGCCAGCCCGCGGAG 15 847 729640 N/A N/A 1611 1626 CAGTTTCCTACATCGA 22 848

TABLE 12 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 73 39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 63 468 729195 N/A N/A 3775 3790 TCGGGTAGCACTTAGG 53 849 729334 N/A N/A 2204 2219 AGTGGGCAGCCCTAGA 12 850 729335 N/A N/A 2224 2239 TGTGAGGCAGCGAAGC 32 851 729336 N/A N/A 2234 2249 CCTACAATTGTGTGAG 10 852 729337 N/A N/A 2258 2273 GAAATCCAACAGCCTG 25 853 729338 N/A N/A 2274 2289 AGCCCCGGAAGGTGGG 11 854 729339 N/A N/A 2284 2299 AATGGACCTGAGCCCC 25 855 729340 N/A N/A 2304 2319 TGGAGCCCTAGACCTA 13 856 729341 N/A N/A 2314 2329 GTGAAATGTATGGAGC 20 857 729342 N/A N/A 2324 2339 GAGTCTCTGGGTGAAA 16 858 729343 N/A N/A 2334 2349 CCAGGCTCCGGAGTCT 0 859 729344 N/A N/A 2365 2380 TGGAAGTTCGGTGTCA 27 860 729345 N/A N/A 2376 2391 GCCCATGACTTTGGAA 8 861 729346 N/A N/A 2386 2401 CCCAATCAAGGCCCAT 16 862 729347 N/A N/A 2405 2420 TAGGTCTAATTCAGAC 6 863 729348 N/A N/A 2415 2430 AGAAAAGGGCTAGGTC 0 864 729349 N/A N/A 2444 2459 TCCATCCTCCTAGAAG 0 865 729350 N/A N/A 2454 2469 CCGAACAGCATCCATC 3 866 729351 N/A N/A 2464 2479 GAGCTCTAACCCGAAC 0 867 729352 N/A N/A 2507 2522 AGGGACTCAGCCTCAA 18 868 729353 N/A N/A 2517 2532 ATGCCACAGAAGGGAC 15 869 729354 N/A N/A 2527 2542 TCTGTCCACCATGCCA 6 870 729355 N/A N/A 2538 2553 ATGAGCGAGAGTCTGT 25 871 729356 N/A N/A 2615 2630 GTGTCAGAGGGCCGCG 28 872 729357 N/A N/A 2625 2640 TCCGACCTCAGTGTCA 20 873 729358 N/A N/A 2635 2650 AAATGATAACTCCGAC 27 874 729359 N/A N/A 2658 2673 GTTTAATACAGAGCAA 36 875 729360 N/A N/A 2668 2683 CAACACGGCTGTTTAA 0 876 729361 N/A N/A 2695 2710 CTGTCAGTCCAGCAGT 29 877 729362 N/A N/A 2708 2723 TGCCTGCCCCCTACTG 5 878 729363 N/A N/A 2755 2770 GAGGCCGTGCAGGCGC 23 879 729364 N/A N/A 2768 2783 GACCCCCTGGGCTGAG 17 880 729365 N/A N/A 2778 2793 CTTCCCTAATGACCCC 19 881 729366 N/A N/A 2799 2814 TCTGCACAGAATCGGG 18 882 729367 N/A N/A 2823 2838 CAAGGGTGGACAGAGG 14 883 729368 N/A N/A 2833 2848 TCTGGCCGAGCAAGGG 24 884 729369 N/A N/A 2843 2858 GGCACACAATTCTGGC 3 885 729370 N/A N/A 2874 2889 GCCCTAGAATAGAGGG 9 886 729371 N/A N/A 2884 2899 AGAGGCCTTGGCCCTA 5 887 729372 N/A N/A 2911 2926 ACCCATAGTTGTATCT 13 888 729373 N/A N/A 2935 2950 GGTTTATAACATGGGT 11 889 729374 N/A N/A 2974 2989 GCACCCCAAACTTGCA 11 890 729375 N/A N/A 2984 2999 GCTGTTCCCCGCACCC 17 891 729376 N/A N/A 2995 3010 TCCCACCCAGAGCTGT 7 892 729377 N/A N/A 3016 3031 CCCCAGACCAAATTTC 0 893 729378 N/A N/A 3026 3041 CGAGTGGGTCCCCCAG 17 894 729379 N/A N/A 3052 3067 ACTCACTGTGGGCTGA 22 895 729380 N/A N/A 3080 3095 GGCTAGACCGGGACAA 29 896 729381 N/A N/A 3090 3105 AAACGAAAGTGGCTAG 11 897 729382 N/A N/A 3108 3123 TCCACCCGGCCCCAGG 3 898 729383 N/A N/A 3329 3344 CCCAGTACCTTTTGGG 0 899 729384 N/A N/A 3339 3354 AAATTCCCTGCCCAGT 6 900 729385 N/A N/A 3372 3387 TGGCCTTGCAGCATGG 27 901 729386 N/A N/A 3386 3401 GTCTGGGCCTGCTTTG 23 902 729387 N/A N/A 3396 3411 AACTCCCTGTGTCTGG 18 903 729388 N/A N/A 3447 3462 CATCAGAAGTGAATGT 8 904 729389 N/A N/A 3458 3473 ACAGCACAGCCCATCA 14 905 729390 N/A N/A 3468 3483 GGGTCATTACACAGCA 23 906 729391 N/A N/A 3509 3524 GCCCTTCACTTGAGAC 13 907 729392 N/A N/A 3519 3534 CATGCCCTTGGCCCTT 8 908 729393 N/A N/A 3530 3545 CTCCCCTTACCCATGC 0 909 729394 N/A N/A 3556 3571 GTCCTGAGTCCCCTTC 0 910 729395 N/A N/A 3567 3582 AACTCTCCACAGTCCT 10 911 729396 N/A N/A 3631 3646 AGGCCAGAGGGACCCT 0 912 729397 N/A N/A 3648 3663 ACTGCCTCCCTGGAGT 0 913 729398 N/A N/A 3695 3710 TGCTACCTACCCAGGG 2 914 729399 N/A N/A 3705 3720 CAGCTCTAACTGCTAC 0 915 729400 N/A N/A 3729 3744 GAAGGCTACAGGAAAC 0 916 729401 N/A N/A 3739 3754 AGCCTGTTAGGAAGGC 0 917 729402 N/A N/A 3749 3764 CGCCTGCCGGAGCCTG 18 918 729403 N/A N/A 3762 3777 AGGAAGGCCCTAACGC 0 919 729641 N/A N/A 2214 2229 CGAAGCATCCAGTGGG 20 920 729642 N/A N/A 2474 2489 AGGTCCACACGAGCTC 30 921 729643 N/A N/A 2593 2608 CAGGCAGCTTAGGGAG 1 922 729644 N/A N/A 2945 2960 CATTTAGTGTGGTTTA 28 923 729645 N/A N/A 3362 3377 GCATGGAGCCTCAGTT 33 924 729646 N/A N/A 3499 3514 TGAGACCCCTGGGTGG 21 925

TABLE 13 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 83 39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 59 468 666150 N/A N/A 3779 3794 GCATTCGGGTAGCACT 46 926 666168 N/A N/A 5286 5301 ATCACCACTGTGTACC 62 927 729196 N/A N/A 3776 3791 TTCGGGTAGCACTTAG 49 928 729197 N/A N/A 3777 3792 ATTCGGGTAGCACTTA 36 929 729198 N/A N/A 3778 3793 CATTCGGGTAGCACTT 33 930 729199 N/A N/A 3780 3795 CGCATTCGGGTAGCAC 46 931 729200 N/A N/A 3781 3796 ACGCATTCGGGTAGCA 40 932 729201 N/A N/A 3782 3797 CACGCATTCGGGTAGC 59 933 729202 N/A N/A 3783 3798 ACACGCATTCGGGTAG 36 934 729203 N/A N/A 3784 3799 GACACGCATTCGGGTA 35 935 729204 N/A N/A 5282 5297 CCACTGTGTACCCCAT 50 936 729205 N/A N/A 5283 5298 ACCACTGTGTACCCCA 72 937 729206 N/A N/A 5284 5299 CACCACTGTGTACCCC 71 938 729207 N/A N/A 5285 5300 TCACCACTGTGTACCC 57 939 729208 N/A N/A 5287 5302 AATCACCACTGTGTAC 20 940 729209 N/A N/A 5288 5303 AAATCACCACTGTGTA 32 941 729210 N/A N/A 5289 5304 CAAATCACCACTGTGT 12 942 729211 N/A N/A 5290 5305 TCAAATCACCACTGTG 44 943 729212 N/A N/A 5291 5306 ATCAAATCACCACTGT 42 944 729404 N/A N/A 3812 3827 CTTGGTCCTCCCCCTT 21 945 729405 N/A N/A 3822 3837 CATCTAGGTTCTTGGT 27 946 729406 N/A N/A 3835 3850 CTCTAGGGCCATTCAT 19 947 729407 N/A N/A 3855 3870 GCACCAAACAGATGTT 19 948 729408 N/A N/A 3885 3900 ACCAACTCAACCCACC 13 949 729409 N/A N/A 3895 3910 AATCCCATCAACCAAC 15 950 729410 N/A N/A 3905 3920 TCTTTAGAGAAATCCC 38 951 729411 N/A N/A 3943 3958 AAGGACACCTGCCCTC 6 952 729412 N/A N/A 3954 3969 CTGGAGCTCCCAAGGA 17 953 729413 N/A N/A 3965 3980 AAGAATCTCATCTGGA 4 954 729414 N/A N/A 3975 3990 TGCCCTCAACAAGAAT 0 955 729415 N/A N/A 3995 4010 CTGAGAGTTCCCTCCG 22 956 729416 N/A N/A 4059 4074 CTCCTGCTCAGTCTAC 21 957 729417 N/A N/A 4100 4115 CTGGGACAGCGAGCGC 47 958 729418 N/A N/A 4120 4135 TCTTGTCTCAAGCTGG 32 959 729419 N/A N/A 4140 4155 TGACACCAAAAGCCCG 37 960 729420 N/A N/A 4150 4165 AGTGACTGCCTGACAC 11 961 729421 N/A N/A 4185 4200 GCCCACCCCTTGCTCT 11 962 729422 N/A N/A 4205 4220 CTACTCACACCACAGG 38 963 729423 N/A N/A 4215 4230 CCGCCTTCCACTACTC 26 964 729424 N/A N/A 4225 4240 GGCCAGAGAACCGCCT 14 965 729425 N/A N/A 4241 4256 CAGCAAGCAGCCCGTT 21 966 729426 N/A N/A 4251 4266 CTGCTAACAGCAGCAA 10 967 729427 N/A N/A 4261 4276 CATTCTCCAACTGCTA 43 968 729428 N/A N/A 4272 4287 GCAGAGGCATCCATTC 19 969 729429 N/A N/A 4292 4307 CCCCAGGTGCCCTTTA 7 970 729430 N/A N/A 4304 4319 CTGCGGGCGCGGCCCC 22 971 729431 N/A N/A 4324 4339 GAGTTACGAGTTAGTG 49 972 729432 N/A N/A 4357 4372 TCATGGAATTTTGTGT 31 973 729433 N/A N/A 4367 4382 TTGTCTAGTGTCATGG 64 974 729434 N/A N/A 4379 4394 GCATCAGCTTTCTTGT 39 975 729435 N/A N/A 4401 4416 TAAGGCCAATTCTCTT 19 976 729436 N/A N/A 4412 4427 ATCTAGGTATTTAAGG 19 977 729437 N/A N/A 4422 4437 TCTCCAGTCCATCTAG 15 978 729438 N/A N/A 4432 4447 AAGGATGGTCTCTCCA 14 979 729439 N/A N/A 4457 4472 CTCAGAGGTCAAGCTA 30 980 729440 N/A N/A 4484 4499 GGTCTGCAGGTGGATG 26 981 729441 N/A N/A 4730 4745 GGGCTTACCTTGAAGA 20 982 729442 N/A N/A 4744 4759 CAACCTCCTCCCCGGG 12 983 729443 N/A N/A 4754 4769 GAGGTCCAGCCAACCT 1 984 729444 N/A N/A 4790 4805 TTATGTGCGCTCCTCT 26 985 729445 N/A N/A 4806 4821 GAGCTGCCTGTGTGCG 31 986 729446 N/A N/A 4817 4832 CCAGCCTCGAGGAGCT 4 987 729447 N/A N/A 4853 4868 CCGGCATCAGCAGCAG 57 988 729448 N/A N/A 4897 4912 AAAGGTGTACCCTGTG 36 989 729449 N/A N/A 5076 5091 AAGATGTGCCCTAGGC 35 990 729450 N/A N/A 5087 5102 GCAGGTTAGAAAAGAT 16 991 729451 N/A N/A 5097 5112 GCTCTAGGGTGCAGGT 49 992 729452 N/A N/A 5107 5122 TCCCCACGATGCTCTA 14 993 729453 N/A N/A 5140 5155 CGAGTTATGGGAAGGC 66 994 729454 N/A N/A 5170 5185 AGGAGTGAGACGAGCA 75 995 729455 N/A N/A 5190 5205 AACAAGTCCTCATGAG 19 996 729456 N/A N/A 5213 5228 TCCTTTAGCATATGCG 67 997 729647 N/A N/A 3845 3860 GATGTTACCTCTCTAG 38 998 729648 N/A N/A 4016 4031 AGTTTTCTCACCCTCC 49 999 729649 N/A N/A 4049 4064 GTCTACACCCCTAGTT 24 1000 729650 N/A N/A 4195 4210 CACAGGTTAGGCCCAC 44 1001 729651 N/A N/A 4467 4482 GGACAGGGTACTCAGA 26 1002

TABLE 14 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 23 39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 46 468 666178 N/A N/A 6540 6555 GCATTCCATATACACA 51 1003 666184 N/A N/A 6972 6987 TGCCTTTTAATGTTGA 36 1004 666187 N/A N/A 7176 7191 CTAGACAAATATGCAG 29 1005 729213 N/A N/A 6539 6554 CATTCCATATACACAC 71 1006 729214 N/A N/A 6541 6556 TGCATTCCATATACAC 28 1007 729215 N/A N/A 6542 6557 TTGCATTCCATATACA 27 1008 729216 N/A N/A 6543 6558 TTTGCATTCCATATAC 3 1009 729217 N/A N/A 6544 6559 TTTTGCATTCCATATA 19 1010 729218 N/A N/A 6545 6560 ATTTTGCATTCCATAT 20 1011 729219 N/A N/A 6969 6984 CTTTTAATGTTGAATT 0 1012 729220 N/A N/A 6970 6985 CCTTTTAATGTTGAAT 0 1013 729221 N/A N/A 6971 6986 GCCTTTTAATGTTGAA 50 1014 729222 N/A N/A 6973 6988 ATGCCTTTTAATGTTG 0 1015 729223 N/A N/A 6974 6989 TATGCCTTTTAATGTT 10 1016 729224 N/A N/A 6975 6990 CTATGCCTTTTAATGT 0 1017 729225 N/A N/A 6976 6991 TCTATGCCTTTTAATG 13 1018 729226 N/A N/A 7171 7186 CAAATATGCAGATATC 3 1019 729227 N/A N/A 7173 7188 GACAAATATGCAGATA 0 1020 729228 N/A N/A 7174 7189 AGACAAATATGCAGAT 1 1021 729229 N/A N/A 7175 7190 TAGACAAATATGCAGA 27 1022 729230 N/A N/A 7177 7192 TCTAGACAAATATGCA 18 1023 729231 N/A N/A 7178 7193 GTCTAGACAAATATGC 0 1024 729232 N/A N/A 7179 7194 AGTCTAGACAAATATG 12 1025 729233 N/A N/A 7180 7195 AAGTCTAGACAAATAT 0 1026 729234 N/A N/A 7181 7196 TAAGTCTAGACAAATA 0 1027 729457 N/A N/A 5292 5307 TATCAAATCACCACTG 0 1028 729458 N/A N/A 5302 5317 TCACTGTGCTTATCAA 22 1029 729459 N/A N/A 5314 5329 TACCTGATCTGATCAC 0 1030 729460 N/A N/A 5325 5340 GATATGCTAAGTACCT 43 1031 729461 N/A N/A 5368 5383 GTTTGTTCCCAACACA 34 1032 729462 N/A N/A 5393 5408 GTATCTGAATCTTATA 22 1033 729463 N/A N/A 5403 5418 GATTGATGATGTATCT 0 1034 729464 N/A N/A 5413 5428 ACAATTGAAAGATTGA 0 1035 729465 N/A N/A 5464 5479 ATCTGGTCAACAGTGT 21 1036 729466 N/A N/A 5606 5621 CAAGGAGGTTGAGATG 0 1037 729467 N/A N/A 5804 5819 GTAGTACATCAATTAA 0 1038 729468 N/A N/A 5814 5829 ATGTACAGTTGTAGTA 0 1039 729469 N/A N/A 5868 5883 AACACTAGGCAACAGA 0 1040 729470 N/A N/A 5878 5893 CCAATGGTGCAACACT 0 1041 729471 N/A N/A 5888 5903 CCACTGCTCACCAATG 0 1042 729472 N/A N/A 5910 5925 TGGAGGTTGTGCTATG 0 1043 729473 N/A N/A 5921 5936 TTGAGCTGAGTTGGAG 0 1044 729474 N/A N/A 6478 6493 ACATCCTAGCATTAAG 0 1045 729475 N/A N/A 6495 6510 AAACTATTATGCGAGG 55 1046 729476 N/A N/A 6549 6564 TCCAATTTTGCATTCC 64 1047 729477 N/A N/A 6559 6574 TTCACTTGATTCCAAT 14 1048 729478 N/A N/A 6614 6629 AAGGAAAGCTGATCCT 0 1049 729479 N/A N/A 6624 6639 GTATGTTGGAAAGGAA 19 1050 729480 N/A N/A 6639 6654 AAAAGTGATGTGGACG 23 1051 729481 N/A N/A 6666 6681 CATTCCAGTGGAAATT 2 1052 729482 N/A N/A 6679 6694 AATTGTGCTAAACCAT 10 1053 729483 N/A N/A 6689 6704 TCAGTGACCAAATTGT 30 1054 729484 N/A N/A 6710 6725 CAAGTATCTAAAAACC 0 1055 729485 N/A N/A 6752 6767 CATGACAATGTGGTTT 37 1056 729486 N/A N/A 6762 6777 AGACAGCCTACATGAC 23 1057 729487 N/A N/A 6772 6787 GGAAGCATTAAGACAG 6 1058 729488 N/A N/A 6799 6814 CCCAAAATAATTGAGG 0 1059 729489 N/A N/A 6810 6825 GGAAATCAACCCCCAA 21 1060 729490 N/A N/A 6840 6855 TTGCCTTTGACCCAGC 34 1061 729491 N/A N/A 6887 6902 GCCCAAAAACTAAGAA 0 1062 729492 N/A N/A 6897 6912 TAAGGATCAAGCCCAA 26 1063 729493 N/A N/A 6947 6962 CTGTATTACCTATACA 0 1064 729494 N/A N/A 6958 6973 GAATTTTGTGACTGTA 56 1065 729495 N/A N/A 6981 6996 ACCATTCTATGCCTTT 53 1066 729496 N/A N/A 6998 7013 GAGACTTTTTGCTCTA 0 1067 729497 N/A N/A 7019 7034 GTGATGAACCAGGGAA 44 1068 729498 N/A N/A 7045 7060 GGAAAGGCTAGGGAGG 1 1069 729499 N/A N/A 7059 7074 ACGGCTGCCTCTAGGG 9 1070 729500 N/A N/A 7128 7143 AGGATAGTTCCATATT 15 1071 729501 N/A N/A 7145 7160 TATGAAAAGTAGAGGA 0 1072 729502 N/A N/A 7156 7171 CTAGCATTTCTTATGA 2 1073 729503 N/A N/A 7184 7199 TATTAAGTCTAGACAA 0 1074 729504 N/A N/A 7194 7209 CGTCAAGAAGTATTAA 0 1075 729505 N/A N/A 7208 7223 TGACATGTAGCAATCG 28 1076 729652 N/A N/A 6458 6473 TTGGAGAGAGCACAGT 11 1077 729653 N/A N/A 6654 6669 AATTCTACAGTCACGA 26 1078 729654 N/A N/A 7106 7121 CATGTGCATAAAAATC 0 1079

TABLE 15 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 78 39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 58 468 666188 N/A N/A 7391 7406 AGAAGCATTCACACAA 41 1080 729235 N/A N/A 7387 7402 GCATTCACACAAAATA 52 1081 729236 N/A N/A 7388 7403 AGCATTCACACAAAAT 54 1082 729237 N/A N/A 7389 7404 AAGCATTCACACAAAA 27 1083 729238 N/A N/A 7390 7405 GAAGCATTCACACAAA 39 1084 729239 N/A N/A 7392 7407 TAGAAGCATTCACACA 41 1085 729240 N/A N/A 7393 7408 ATAGAAGCATTCACAC 22 1086 729241 N/A N/A 7394 7409 CATAGAAGCATTCACA 46 1087 729242 N/A N/A 7395 7410 TCATAGAAGCATTCAC 50 1088 729243 N/A N/A 7396 7411 ATCATAGAAGCATTCA 59 1089 729506 N/A N/A 7218 7233 GTTTATAAGCTGACAT 39 1090 729507 N/A N/A 7228 7243 GCAGGAAACTGTTTAT 55 1091 729508 N/A N/A 7253 7268 ACTGGGCAGCACAAAA 25 1092 729509 N/A N/A 7271 7286 ACCCATTGAATGAAAA 23 1093 729510 N/A N/A 7281 7296 ATTACGGCCAACCCAT 0 1094 729511 N/A N/A 7291 7306 GGCTGGTGAAATTACG 10 1095 729512 N/A N/A 7306 7321 CATCCATCAATGAGGG 51 1096 729513 N/A N/A 7316 7331 CCCAATGCAACATCCA 69 1097 729514 N/A N/A 7328 7343 TGACCCAAAATACCCA 44 1098 729515 N/A N/A 7338 7353 GTGTAAAAGATGACCC 37 1099 729516 N/A N/A 7349 7364 AGCAGTGCTGTGTGTA 48 1100 729517 N/A N/A 7372 7387 ATTGCACACACAAAGT 10 1101 729518 N/A N/A 7397 7412 TATCATAGAAGCATTC 24 1102 729519 N/A N/A 7426 7441 CTATTTGATTTCTAGG 18 1103 729520 N/A N/A 7437 7452 TTTTAACCCAGCTATT 6 1104 729521 N/A N/A 7460 7475 GGTTACCAACATTTCT 42 1105 729522 N/A N/A 7470 7485 GTGAGGTGAGGGTTAC 38 1106 729523 N/A N/A 7508 7523 ACACTGGAGCTGTTGG 51 1107 729524 N/A N/A 7519 7534 ACAGGCTCGAGACACT 31 1108 729525 N/A N/A 7529 7544 TGCACATAGGACAGGC 22 1109 729526 N/A N/A 7550 7565 TAAAGCACTCAGAGCT 16 1110 729527 N/A N/A 7560 7575 TTGATGTCCGTAAAGC 53 1111 729528 N/A N/A 7876 7891 AGCGAAGACTCAAGGG 48 1112 729529 N/A N/A 7887 7902 CATGGAGTGGCAGCGA 42 1113 729530 N/A N/A 7899 7914 AGTTGCCCACCTCATG 22 1114 729531 N/A N/A 7909 7924 ATCTCCTCACAGTTGC 28 1115 729532 N/A N/A 7920 7935 CCTTTGTCTTGATCTC 48 1116 729533 N/A N/A 7936 7951 GCCATGTCACTGCCTC 30 1117 729534 N/A N/A 7953 7968 CGCCAGCTGTGTGCCA 28 1118 729535 N/A N/A 7966 7981 TGGAAGTGCCCCCCGC 34 1119 729536 N/A N/A 7976 7991 GGTTTGAATCTGGAAG 31 1120 729537 N/A N/A 8000 8015 GGTGAGCACCCTGGAG 30 1121 729538 N/A N/A 8027 8042 TCTAAGGAGGACAGCG 35 1122 729539 N/A N/A 8043 8058 GTGAAACAGTGTGATC 40 1123 729540 N/A N/A 8064 8079 ATAGTCCCTGCTCCTG 49 1124 729541 N/A N/A 8144 8159 GTGGGAGTCTGCCACA 6 1125 729542 N/A N/A 8159 8174 GACCTGGTTTGCAGCG 34 1126 729543 N/A N/A 8171 8186 CGCTGAGCCCCAGACC 0 1127 729544 N/A N/A 8181 8196 GGCTGAGCCTCGCTGA 22 1128 729545 N/A N/A 8194 8209 AACTTCGGCTACAGGC 39 1129 729546 N/A N/A 8213 8228 GACTCTACTGTGTGGG 38 1130 729547 N/A N/A 8266 8281 CACAGAGAACCTCATC 11 1131 729548 N/A N/A 8276 8291 AATAGCCGACCACAGA 10 1132 729549 N/A N/A 8489 8504 GCCTGATACCTGTGGG 3 1133 729550 N/A N/A 8525 8540 ATTGCACAGCCTCCCA 8 1134 729551 N/A N/A 8555 8570 ACCCAAGAGCTCATGG 6 1135 729552 N/A N/A 8569 8584 CTTGGCCTGCCTGCAC 10 1136 729553 N/A N/A 8598 8613 TTCCTGGACCACTGCC 15 1137 729554 N/A N/A 8617 8632 GCGGGAGCCCCCGCAT 22 1138 729555 N/A N/A 8637 8652 GCCCTGGGTGTCATGA 17 1139 729556 N/A N/A 8648 8663 CACTCCTGGAAGCCCT 0 1140 729557 N/A N/A 8661 8676 GACCCATCCCAGCCAC 7 1141 729558 N/A N/A 8671 8686 ATATGCCAGTGACCCA 15 1142 729559 N/A N/A 8681 8696 GCCATTCCTGATATGC 28 1143 729560 N/A N/A 8691 8706 TGCACGCCAAGCCATT 28 1144 729561 N/A N/A 8711 8726 GAAGCACCCAGGTCCC 24 1145 729562 N/A N/A 8722 8737 ATGGTAAGGAAGAAGC 18 1146 729563 N/A N/A 8732 8747 AACGAGGGCAATGGTA 11 1147 729564 N/A N/A 8763 8778 CCATGAGACCTAGGCT 3 1148 729565 N/A N/A 8773 8788 ACTCCATGGGCCATGA 3 1149 729566 N/A N/A 8794 8809 GGATTGGGAAAGACCT 15 1150 729567 N/A N/A 8817 8832 CGAGGTGGAGGGCACA 11 1151 729568 N/A N/A 8827 8842 CAACACAGGGCGAGGT 8 1152 729569 N/A N/A 8859 8874 TATGCAGCTTCTGCCT 3 1153 729655 N/A N/A 7480 7495 TGGCAATTAGGTGAGG 48 1154 729656 N/A N/A 8101 8116 CAAGCTACATGAAATC 11 1155 729657 N/A N/A 8627 8642 TCATGACCTAGCGGGA 11 1156

TABLE 16 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop IRF5 (% ID Number Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 665893 1228 1243 10461 10476 GCACTGACACAGGCGG 83 39 665933 1561 1576 11126 11141 GCGGTCTTTGAGGTCT 64 468 666208 N/A N/A 9349 9364 CAGTTTAGCTCAGGCA 69 1157 729244 N/A N/A 9344 9359 TAGCTCAGGCAAGACC 32 1158 729245 N/A N/A 9345 9360 TTAGCTCAGGCAAGAC 17 1159 729246 N/A N/A 9346 9361 TTTAGCTCAGGCAAGA 23 1160 729247 N/A N/A 9347 9362 GTTTAGCTCAGGCAAG 24 1161 729248 N/A N/A 9348 9363 AGTTTAGCTCAGGCAA 47 1162 729249 N/A N/A 9353 9368 GCCTCAGTTTAGCTCA 23 1163 729250 N/A N/A 9354 9369 AGCCTCAGTTTAGCTC 9 1164 729570 N/A N/A 8869 8884 CTGTAGCTCCTATGCA 14 1165 729571 N/A N/A 8895 8910 AGAAGCAAGATCCCCT 2 1166 729572 N/A N/A 8905 8920 ATGTCGGAGGAGAAGC 0 1167 729573 N/A N/A 8915 8930 AAAGGAGTCAATGTCG 0 1168 729574 N/A N/A 8925 8940 GCAGGGCAGTAAAGGA 12 1169 729575 N/A N/A 8948 8963 GTCTGCACAGCAGGGA 24 1170 729576 N/A N/A 9021 9036 AACCCACACTCACCTC 25 1171 729577 N/A N/A 9046 9061 CGTCCAGGGCTCCACC 13 1172 729578 N/A N/A 9060 9075 GACAGCAGAGAGCTCG 9 1173 729579 N/A N/A 9082 9097 GCGGAAACCTAAGGCC 12 1174 729580 N/A N/A 9118 9133 ATTGAGAGGGCCACGG 27 1175 729581 N/A N/A 9133 9148 GAAACAAGGAGAACTA 29 1176 729582 N/A N/A 9151 9166 TTCAGAATCCCAGGAG 21 1177 729583 N/A N/A 9167 9182 GACTGTGCTCCTATCG 27 1178 729584 N/A N/A 9195 9210 GACAATGCCCTGGGAA 55 1179 729585 N/A N/A 9205 9220 ACAGGGTAATGACAAT 28 1180 729586 N/A N/A 9219 9234 CGTGGGTCACACACAC 39 1181 729587 N/A N/A 9233 9248 AGCCCCAACTGCTGCG 25 1182 729588 N/A N/A 9249 9264 GGAGTCAGACCTACCA 18 1183 729589 N/A N/A 9259 9274 CCTTCTGCAGGGAGTC 73 1184 729590 N/A N/A 9285 9300 GCCCTTTGCCTCACTT 17 1185 729591 N/A N/A 9324 9339 CTCCGGTCCCAGCTCG 6 1186 729592 N/A N/A 9334 9349 AAGACCCTGCCTCCGG 23 1187 729593 N/A N/A 9355 9370 TAGCCTCAGTTTAGCT 0 1188 729594 N/A N/A 9375 9390 GAACTATGAGGCAACT 10 1189 729595 N/A N/A 9385 9400 TAACAGGCGAGAACTA 9 1190 729596 N/A N/A 9427 9442 GAAAGGAGGACAGGTT 0 1191 729597 N/A N/A 9467 9482 TGAAGGGACACCACCA 31 1192 729598 N/A N/A 9533 9548 TAGACCCCCAACCACC 5 1193 729599 N/A N/A 9553 9568 CCTATAGCTTCTCTGT 51 1194 729600 N/A N/A 9567 9582 AGGTACCTATGGTACC 9 1195 729601 N/A N/A 9578 9593 AGCCCCCTTCCAGGTA 28 1196 729602 N/A N/A 9590 9605 TAGCCTCCCATCAGCC 11 1197 729603 N/A N/A 9602 9617 CCTGGGCCACCCTAGC 11 1198 729604 N/A N/A 9634 9649 CGAACTGCCTCCCAGG 7 1199 729605 N/A N/A 9645 9660 TGCCACCTCCACGAAC 39 1200 729606 N/A N/A 9655 9670 CGGCTGTCAGTGCCAC 17 1201 729607 N/A N/A 9683 9698 CACTGCATCTACAGAG 17 1202 729608 N/A N/A 9998 10013 CAGCCATGGGTCCTTA 18 1203 729609 N/A N/A 10009 10024 TTCCCCGTGCCCAGCC 0 1204 729610 N/A N/A 10025 10040 AATCCCCCAGCACTGC 22 1205 729611 N/A N/A 10041 10056 TTGCCAATCCTACCCC 31 1206 729612 N/A N/A 10073 10088 CACCCAAGGGAGTCCA 22 1207 729613 N/A N/A 10099 10114 AGCCCCATCCGCCCTC 3 1208 729614 N/A N/A 10157 10172 GGCCCATCCCGTCCTT 0 1209 729615 N/A N/A 10183 10198 GGTCGGTCACTGTGGG 8 1210 729616 N/A N/A 10581 10596 CTTTGGGCCCTCACCA 0 1211 729617 N/A N/A 10591 10606 AGGATCACAGCTTTGG 12 1212 729618 N/A N/A 10616 10631 ATGCCCTGGGCAAGAG 8 1213 729619 N/A N/A 10627 10642 AGGCTGGAACCATGCC 0 1214 729620 N/A N/A 10637 10652 CCCTAGTCAGAGGCTG 11 1215 729621 N/A N/A 10647 10662 AAATCAAGGTCCCTAG 2 1216 729622 N/A N/A 10658 10673 GCTCTGCATCAAAATC 7 1217 729623 N/A N/A 10780 10795 ATGTACCTGTACAGTA 14 1218 729624 N/A N/A 10800 10815 CCGACTTTGGGATAGG 15 1219 729625 N/A N/A 10810 10825 CAAGCCAAGGCCGACT 36 1220 729626 N/A N/A 10820 10835 CCCCAGTTTTCAAGCC 13 1221 729627 N/A N/A 10833 10848 TAGCCCCAGGATTCCC 5 1222 729628 N/A N/A 10883 10898 AAGTTCACACTGCTCA 38 1223 729629 N/A N/A 10914 10929 CGGCTCTGAGCCTTGA 0 1224 729630 N/A N/A 10933 10948 AGTAATAGACCGCATT 21 1225 729631 N/A N/A 10952 10967 AGGACAGCCATCAGGG 8 1226 729632 N/A N/A 10962 10977 GCTGTGCATGAGGACA 17 1227 729633 N/A N/A 10972 10987 GCCAGATCCAGCTGTG 0 1228 729634 N/A N/A 11023 11038 ACCACCTGGGAGGCAA 16 1229 729658 N/A N/A 8885 8900 TCCCCTGAGAGGCTGC 20 1230 729659 N/A N/A 9543 9558 CTCTGTATACTAGACC 64 1231 729660 N/A N/A 10134 10149 ACGCCTCCCCATTCTG 6 1232 729661 N/A N/A 10894 10909 CTCTGGCCGCCAAGTT 5 1233

TABLE 17 Inhibition of IRF5 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 3 SEQ SEQ ID ID Com- NO: 3 NO: 3 IRF5 SEQ pound Start Stop Sequence (%Inhi- ID Number Site Site (5′ to 3′) bition) NO 728399  96 111 TCTGTCTG 26 1234 CGGTGCGC 728400  98 113 GGTCTGTC 23 1235 TGCGGTGC 728539 591 606 GCATCTGT 21 1236 GAGGCTCA 728540 593 608 CTGCATCT 30 1237 GTGAGGCT 728541 595 610 CACTGCAT  8 1238 CTGTGAGG 728542 597 612 TGCACTGC 20 1239 ATCTGTGA 728543 599 614 ACTGCACT 12 1240 GCATCTGT

Example 2: Antisense Inhibition of Human IRF5 in KARPAS-229 Cells by Modified Oligonucleotides

In the second stage of the screening, modified oligonucleotides were designed to sites adjacent to the most active leads/sites from the first stage of screening described above. Briefly, active leads from the first phase of the screening were microwalked until previously tested or rejected sites were approximately reached. Several different chemistry modifications were tested, which are specified in the Chemistry Notation column of the tables below, wherein the notation “d” refers to a 2′-deoxyribose sugar, the notation “s” refers to a phosphorothioate internucleoside linkage, the notation “k” refers to a cEt modified sugar, and the notation “mC” refers to a 5-methyl cytosine.

Cultured KARPAS-229 cells at a density of 10,000 cells per well were treated using free uptake with 4,000 nM of modified oligonucleotide. After a treatment period of approximately 48 hours, RNA was isolated from the cells and IRF5 mRNA levels were measured by quantitative real-time RTPCR. Human primer probe set RTS4524 (forward sequence TTCGAGATCTTCTTCTGCTTTGG, designated herein as SEQ ID NO: 14; reverse sequence GCACCACCTGTACAGTAATGAGCTT; designated herein as SEQ ID NO: 15; probe sequence CCTGACCGCAAACCCCGAGAGAA, designated herein as SEQ ID NO: 16) was used to measure mRNA levels. IRF5 mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of IRF5 relative to untreated control cells. As used herein, a value of ‘0’ indicates that treatment with the modified oligonucleotide did not inhibit IRF5 mRNA levels. ‘N/A’ indicates that the modified oligonucleotide does not target that gene sequence with 100% complementarity.

TABLE 18 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 (% SEQ Compound Start Stop Start Stop Sequence Chemistry Inhi- ID Number Site Site Site Site (5′ to 3′) Notation bition) NO 666178 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks)A_(k) 21 1003 728708 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 48  436 728894 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 45  633 729213 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 28 1006 729476 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 79 1047 785370 1762 1777 11327 11342 CATCTCCACATCAGTC ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k) 25  631 785371 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k) 15  633 785392 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 31 1006 785393 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(k) 39 1003 785394 N/A N/A  6547  6562 CAATTTTGCATTCCAT ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(k) 21 1241 785395 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 37 1047 785425 1762 1777 11327 11342 CATCTCCACATCAGTC ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es)T_(ks) ^(m)C_(e) 32  631 785426 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)A_(es)T_(ks) ^(m)C_(es)A_(ks)G_(e)  2  633 785447 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(e)  7 1006 785448 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ks)A_(es) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(e) 34 1003 785449 N/A N/A  6547  6562 CAATTTTGCATTCCAT ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks)T_(e) 19 1241 785450 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(es)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e)  6 1047 785471 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(es) ^(m)C_(es)A_(ks)G_(k) 26  633 785483 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(es)T_(ks)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(es) ^(m)C_(es)A_(ks) ^(m)C_(k) 24 1006 785484 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(es)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(es)A_(es) ^(m)C_(ks)A_(k) 48 1003 785485 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 76 1047 785513 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(es)G_(ks)T_(e) 36  632 785514 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(e) 23  633 785535 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(e) 30 1006 785536 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(e) 37 1003 785537 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 57 1242 785538 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 40 1047 785558 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(es)T_(es) ^(m)C_(es)A_(es)G_(ks)T_(k) 24  632 785570 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(es) ^(m)C_(es)A_(es) ^(m)C_(es)A_(ks) ^(m)C_(k) 21 1006 785571 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(es)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ks)A_(k) 48 1242 785609 1762 1777 11327 11342 CATCTCCACATCAGTC ^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es)T_(ks) ^(m)C_(k) 23  631 785610 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)Ck_(s)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)T_(es) ^(m)C_(ks)A_(es)G_(ks)T_(k) 15  632 785611 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)A_(es)T_(ks) ^(m)C_(es)A_(ks)G_(k) 17  633 785640 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(k) 17 1006 785641 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ks)A_(es) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(k)  0 1003 785642 N/A N/A  6547  6562 CAATTTTGCATTCCAT ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks)T_(k) 32 1241 785643 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(k) 39 1242 785644 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(es)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(k) 15 1047 785667 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(es) ^(m)C_(es)A_(es)G_(ks)T_(k) 41  632 785679 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(es)A_(es) ^(m)C_(es)A_(ks) ^(m)C_(k) 21 1006 785680 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ks)A_(k) 30 1242 785697 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ds)A_(ks)G_(ds)T_(k) 28  632 785709 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ds) ^(m)C_(ks)A_(ds) ^(m)C_(k) 25 1006 785710 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(k) 42 1242 785738 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es)T_(k) 16  632 785739 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k) 22  633 785760 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 54 1006 785761 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(k)  2 1003 785762 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 11 1242 785763 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 29 1047 785784 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)T_(ds) ^(m)C_(ks)A_(ds)G_(k) 39  633 785796 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ds) ^(m)C_(ks)A_(ds) ^(m)C_(k) 40 1006 785797 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(ds)A_(ks) ^(m)C_(ds)A_(k)  0 1003 785798 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(k) 32 1047 785826 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es)T_(k) 14  632 785827 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k) 43  633 785848 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 32 1006 785849 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(k)  0 1003 785850 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 42 1242 785851 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 51 1047 785872 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(e) 38  633 785884 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(e) 28 1006 785885 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(e) 45 1003 785886 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 14 1047 785914 1763 1778 11328 11343 ACATCTCCACATCAGT A_(ks) ^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(ks)T_(e) 11  632 785915 1764 1779 11329 11344 CACATCTCCACATCAG ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ks)A_(ks)G_(e) 25  633 785936 N/A N/A  6539  6554 CATTCCATATACACAC ^(m)C_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 39 1006 785937 N/A N/A  6540  6555 GCATTCCATATACACA G_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(e) 25 1003 785938 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 80 1242 785939 N/A N/A  6549  6564 TCCAATTTTGCATTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e)  7 1047 786505 N/A N/A  6546  6561 AATTTTGCATTCCATA A_(ks)A_(ks)T_(ks)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)T_(ks)A_(k) 41 1243 786506 N/A N/A  6547  6562 CAATTTTGCATTCCAT ^(m)C_(ks)A_(ks)A_(ks)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)T_(k) 52 1241 786507 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)AT_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 78 1242 786508 N/A N/A  6550  6565 TTCCAATTTTGCATTC T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(ks) ^(m)C_(k) 39 1244 786509 N/A N/A  6551  6566 ATTCCAATTTTGCATT A_(ks)T_(ks)T_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ks)T_(k) 21 1245 786510 N/A N/A  6553  6568 TGATTCCAATTTTGCA T_(ks)G_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 17 1246 786511 N/A N/A  6555  6570 CTTGATTCCAATTTTG ^(m)C_(ks)T_(ks)T_(ks)G_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(k) 20 1247 786512 N/A N/A  6557  6572 CACTTGATTCCAATTT ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ks)T_(ks)T_(k) 36 1248

TABLE 19 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) Chemistry Notation bition) NO 665795  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(k) 31  113 728489  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k)  0 1249 728695 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(ks)G_(k)  0  423 728696 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(k) 21  424 728708 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 38  436 785345  383  398  4708  4723 TATCTCCGTCCTGGCT T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(es)T_(k)  0  116 785346  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k)  0  113 785350  482  497  8375  8390 GGGCACAGCGCAGGTT G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks)T_(es)T_(k) 37 1250 785351  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k)  0 1249 785355 1268 1283 10501 10516 AGTCATGGGCTGAGGC A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(es)G_(ks)G_(es) ^(m)C_(k) 25  421 785356 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(es)G_(k)  0  422 785357 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)G_(k)  0  423 785358 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(es)T_(ks)G_(es)A_(k)  0  424 785405  482  497  8375  8390 GGGCACAGCGCAGGTT G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es)T_(ks)T_(e) 33 1250 785406  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ks)G_(es) ^(m)C_(ks)A_(es)G_(ks)G_(e)  0 1249 785410 1268 1283 10501 10516 AGTCATGGGCTGAGGC A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(es)G_(ks) ^(m)C_(e) 17  421 785411 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)G_(ks)G_(e)  0  422 785412 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(es)T_(ks)G_(es)A_(ks)G_(e)  0  423 785413 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ks)G_(es) ^(m)C_(ks)T_(es)G_(ks)A_(e)  7  424 785457  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(es)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(es)T_(es)G_(ks)G_(k) 13  113 785460  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(es)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(es)A_(es)G_(ks)G_(k)  0 1249 785462 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(es)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(es)G_(es)A_(ks)G_(k) 12  423 785463 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(es)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(es)T_(es)G_(ks)A_(k)  0  424 785489  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(e)  0  117 785490  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(e)  0  113 785495  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(e)  0 1249 785499 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(es)G_(ks)G_(e) 40  422 785500 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(e)  0  423 785501 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(e)  0  424 785545  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(es) ^(m)C_(es)T_(es)G_(es)G_(ks) ^(m)C_(k)  0  117 785550 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(es)T_(es)G_(es)A_(es)G_(ks)G_(k)  5  422 785551 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(es) ^(m)C_(es)T_(es)G_(es)A_(ks)G_(k) 15  423 785575  383  398  4708  4723 TATCTCCGTCCTGGCT T_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es) ^(m)C_(ks)T_(k)  6  116 785576  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)G_(es)G_(ks) ^(m)C_(k)  0  117 785577  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)G_(ks)G_(k)  0  113 785583  482  497  8375  8390 GGGCACAGCGCAGGTT G_(ks)G_(ks)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es)T_(ks)T_(k) 61 1250 785584  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ks)G_(es) ^(m)C_(ks)A_(es)G_(ks)G_(k)  0 1249 785590 1268 1283 10501 10516 AGTCATGGGCTGAGGC A_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(es)G_(ks) ^(m)C_(k) 17  421 785591 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)G_(ks)G_(k)  0  422 785592 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(es)T_(ks)G_(es)A_(ks)G_(k)  0  423 785593 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ks)G_(es) ^(m)C_(ks)T_(es)G_(ks)A_(k)  0  424 785654  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(es)T_(es)G_(es)G_(ks) ^(m)C_(k)  5  117 785659 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(es)G_(es)A_(es)G_(ks)G_(k) 30  422 785660 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(es)T_(es)G_(es)A_(ks)G_(k) 16  423 785684  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ds)G_(ks)G_(ds) ^(m)C_(k) 14  117 785689 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(ds)A_(ks)G_(ds)G_(k) 31  422 785690 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(ds)G_(ks)A_(ds)G_(k) 12  423 785714  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es) ^(m)C_(k)  0  117 785715  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k)  0  113 785720  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k)  0 1249 785724 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(es)G_(k) 15  422 785725 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)G_(k)  0  423 785726 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(es)T_(ks)G_(es)A_(k)  0  424 785770  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ds)T_(ks)G_(ds)G_(k) 27  113 785773  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ks) ^(m)C_(ds)A_(ks)G_(ds)G_(k) 12 1249 785775 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(ds)G_(ks)A_(ds)G_(k)  3  423 785776 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(ds)T_(ks)G_(ds)A_(k)  0  424 785802  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es) ^(m)C_(k)  0  117 785803  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k)  0  113 785808  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k)  0 1249 785812 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(es)G_(k)  0  422 785813 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)G_(k)  0  423 785814 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(es)T_(ks)G_(es)A_(k)  0  424 785858  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(e)  0  113 785861  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(e)  0 1249 785863 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)G_(e) 17  423 785864 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(e)  9  424 785890  384  399  4709  4724 TTATCTCCGTCCTGGC T_(ks)T_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(ks) ^(m)C_(e)  0  117 785891  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ks)T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)G_(ks)G_(e) 33  113 785896  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ks)A_(ks)G_(ks)G_(e)  3 1249 785900 1269 1284 10502 10517 GAGTCATGGGCTGAGG G_(ks)A_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(ks)G_(ks)G_(e)  0  422 785901 1270 1285 10503 10518 TGAGTCATGGGCTGAG T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(ks)G_(e) 11  423 785902 1271 1286 10504 10519 ATGAGTCATGGGCTGA A_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(ks)G_(ks)A_(e) 20  424 785938 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 71 1242 786473  385  400  4710  4725 GTTATCTCCGTCCTGG G_(ks)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)G_(ks)G_(e)  0  113 786474  383  398  4708  4723 TATCTCCGTCCTGGCT T_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es) ^(m)C_(ks)T_(e)  0  116 786495  483  498  8376  8391 AGGGCACAGCGCAGGT A_(ks)G_(ks)G_(ks)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(ks)T_(k)  2 1251 786496  485  500  8378  8393 TAAGGGCACAGCGCAG T_(ks)A_(ks)A_(ks)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ks)A_(ks)G_(k)  0 1252 786497  486  501  8379  8394 TTAAGGGCACAGCGCA T_(ks)T_(ks)A_(ks)A_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ks) ^(m)C_(ks)A_(k)  0 1253

TABLE 20 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) Chemistry Notation bition) NO 665892 1227 1242 10460 10475 CACTGACACAGGCGGA ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ds)G_(ks)G_(ks)A_(k)  1  387 665893 1228 1243 10461 10476 GCACTGACACAGGCGG G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks)G_(ks)G_(k) 14   39 728466  427  442  8320  8335 GGTGTATTTCCCTGTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 10 1254 728489  484  499  8377  8392 AAGGGCACAGCGCAGG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 48 1249 728670 1230 1245 10463 10478 TTGCACTGACACAGGC T_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(ks) ^(m)C_(k) 18  398 728705 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)G_(ks) ^(m)C_(k) 33  433 728706 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 41  434 728707 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 43  435 728708 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 14  436 729037 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k) 68  706 785354 1228 1243 10461 10476 GCACTGACACAGGCGG G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(es) ^(m)C_(ks)G_(es)G_(k)  0   39 785359 1301 1316 10534 10549 TCTTGACCTCCCGCTG T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)G_(es) ^(m)C_(ks)T_(es)G_(k) 46  391 785360 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)G_(es) ^(m)C_(k) 37  433 785361 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k)  0  434 785362 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 18  435 785363 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k)  0  436 785409 1228 1243 10461 10476 GCACTGACACAGGCGG G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks) ^(m)C_(es)G_(ks)G_(e)  0   39 785414 1301 1316 10534 10549 TCTTGACCTCCCGCTG T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(es)T_(ks)G_(e) 40  391 785415 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(e) 35  433 785416 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e)  0  434 785417 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 17  435 785418 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks)G_(es)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(e) 14  436 785464 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(es)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(es) ^(m)C_(es)G_(ks) ^(m)C_(k) 33  433 785465 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(es)T_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 36  434 785466 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(es)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 46  435 785467 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(es) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(es) ^(m)C_(es) ^(m)C_(ks)T_(k) 38  436 785498 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(es) ^(m)C_(ks)G_(e) 16  388 785502 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)G_(es) ^(m)C_(ks)T_(e) 65  432 785503 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(e)  0  433 785504 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 39  434 785505 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e)  9  435 785506 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(e)  0  436 785549 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(es)A_(es)G_(es)G_(es) ^(m)C_(ks)G_(k)  0  388 785552 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es)G_(es) ^(m)C_(ks)T_(k) 34  432 785553 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(es) ^(m)C_(es) ^(m)C_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 20  434 785554 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(es)A_(es) ^(m)C_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 19  435 785588 1228 1243 10461 10476 GCACTGACACAGGCGG G_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks) ^(m)C_(es)G_(ks)G_(k)  0   39 785589 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es) ^(m)C_(ks)G_(k)  0  388 785594 1301 1316 10534 10549 TCTTGACCTCCCGCTG T_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(es)T_(ks)G_(k) 19  391 785595 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)G_(es) ^(m)C_(ks)T_(k) 26  432 785596 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(k) 44  433 785597 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(k)  0  434 785598 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(k) 21  435 785599 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks)G_(es)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(k)  0  436 785658 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(es)G_(es)G_(es) ^(m)C_(ks)G_(k) 18  388 785661 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(es) ^(m)C_(es)G_(es) ^(m)C_(ks)T_(k) 54  432 785662 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(es) ^(m)C_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 11  434 785663 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(es) ^(m)C_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 10  435 785688 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(ds)G_(ks) ^(m)C_(ds)G_(k)  0  388 785691 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ds)G_(ks) ^(m)C_(ds)T_(k) 46  432 785692 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(k) 13  434 785693 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k) 11  435 785723 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks) ^(m)C_(es)G_(k)  0  388 785727 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(es)T_(k) 40  432 785728 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)G_(es) ^(m)C_(k)  7  433 785729 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k)  3  434 785730 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 33  435 785731 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k)  8  436 785777 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ks)G_(ds) ^(m)C_(k)  4  433 785778 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(k) 19  434 785779 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k) 30  435 785780 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(ds) ^(m)C_(ks) ^(m)C_(ds)T_(k) 12  436 785811 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks) ^(m)C_(es)G_(k)  0  388 785815 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(es)T_(k) 23  432 785816 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)G_(es) ^(m)C_(k) 29  433 785817 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k)  1  434 785818 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es) ^(m)C_(k)  0  435 785819 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k)  3  436 785865 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)G_(ks) ^(m)C_(e)  7  433 785866 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 15  434 785867 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 35  435 785868 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(e) 26  436 785899 1229 1244 10462 10477 TGCACTGACACAGGCG T_(ks)G_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(ks) ^(m)C_(ks)G_(e)  0  388 785903 1302 1317 10535 10550 GTCTTGACCTCCCGCT G_(ks)T_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)G_(ks) ^(m)C_(ks)T_(e) 51  432 785904 1303 1318 10536 10551 GGTCTTGACCTCCCGC G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)G_(ks) ^(m)C_(e) 22  433 785905 1306 1321 10539 10554 CTTGGTCTTGACCTCC ^(m)C_(ks)T_(ks)T_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e)  6  434 785906 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(e) 29  435 785907 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 10  436 785938 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 30 1242

TABLE 21 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) Chemistry Notation bition) NO 665908 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)G_(k) 16  393 728466  427  442  8320  8335 GGTGTATTTCCCTGTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 50 1254 728670 1230 1245 10463 10478 TTGCACTGACACAGGC T_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(ks) ^(m)C_(k)  8  398 728707 1307 1322 10540 10555 GCTTGGTCTTGACCTC G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k)  0  435 728708 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 16  436 729037 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k)  0  706 729038 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k)  0  707 729039 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)T_(k)  0  708 785364 1361 1376 10682 10697 TCTGGCCCTTTTGGAA T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ks)G_(es)G_(ks)A_(es)A_(k)  0  454 785365 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(es)G_(k)  0  393 785378 2214 2229 11779 11794 TTCTTGGACTCTCAAG T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)A_(es)G_(k)  0  705 785379 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)A_(k) 35  695 785380 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(k)  9  706 785381 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 34  707 785382 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)T_(k)  0  708 785419 1361 1376 10682 10697 TCTGGCCCTTTTGGAA T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(es)A_(ks)A_(e)  0  454 785420 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(es)T_(ks)T_(es)G_(ks)G_(e)  0  393 785433 2214 2229 11779 11794 TTCTTGGACTCTCAAG T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)A_(ks)G_(e)  0  705 785434 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(ks)A_(e)  0  695 785435 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(e)  0  706 785436 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e)  0  707 785437 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ks)A_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(e)  0  708 785468 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(es)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(es)T_(es)G_(ks)G_(k) 13  393 785475 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(es)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(es)T_(es) ^(m)C_(ks)A_(k) 60  706 785476 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(es)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(es) ^(m)C_(es)T_(ks) ^(m)C_(k)  0  707 785477 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(es)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(es)T_(es) ^(m)C_(ks)T_(k) 48  708 785507 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ks)G_(es)G_(ks)A_(e)  0  455 785508 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(e)  0  393 785521 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)A_(e) 27  695 785522 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(e) 51  706 785523 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 41  707 785524 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(e) 28  708 785555 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(es)T_(es)T_(es)G_(es)G_(ks)A_(k)  0  455 785562 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(es) ^(m)C_(es)T_(es) ^(m)C_(es)A_(ks)A_(k)  8  695 785563 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(es)T_(es) ^(m)C_(es)T_(es) ^(m)C_(ks)A_(k) 54  706 785564 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(es) ^(m)C_(es)T_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 17  707 785600 1361 1376 10682 10697 TCTGGCCCTTTTGGAA T_(ks) ^(m)C_(ks)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(es)A_(ks)A_(k)  0  454 785601 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(es)G_(ks)A_(k)  0  455 785602 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(es)T_(ks)T_(es)G_(ks)G_(k)  0  393 785621 2214 2229 11779 11794 TTCTTGGACTCTCAAG T_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)A_(ks)G_(k)  0  705 785622 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(ks)A_(k)  0  695 785623 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(k)  0  706 785624 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(k)  0  707 785625 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ks)A_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(k)  0  708 785664 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(es)T_(es)G_(es)G_(ks)A_(k)  0  455 785671 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(es)T_(es) ^(m)C_(es)A_(ks)A_(k) 22  695 785672 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(es) ^(m)C_(es)T_(es) ^(m)C_(ks)A_(k) 48  706 785673 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(es)T_(es) ^(m)C_(es)T_(ks) ^(m)C_(k)  0  707 785694 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(ds)G_(ks)G_(ds)A_(k)  0  455 785701 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(ks)A_(ds)A_(k) 20  695 785702 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ds)T_(ks) ^(m)C_(ds)A_(k) 29  706 785703 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k) 36  707 785732 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(es)A_(k)  0  455 785733 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(es)G_(k)  3  393 785746 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)A_(k) 31  695 785747 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(k)  0  706 785748 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 38  707 785749 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)T_(k)  0  708 785781 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(ds)T_(ks)G_(ds)G_(k)  0  393 785788 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ds)T_(ks) ^(m)C_(ds)A_(k) 28  706 785789 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k)  0  707 785790 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(ds)T_(ks) ^(m)C_(ds)T_(k)  0  708 785820 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ks)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(es)A_(k)  0  455 785821 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(es)G_(k)  2  393 785834 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)A_(k)  0  695 785835 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(k) 25  706 785836 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(k)  8  707 785837 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)T_(k)  0  708 785869 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(e) 17  393 785876 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(e) 48  706 785877 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e)  0  707 785878 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)T_(e)  1  708 785908 1362 1377 10683 10698 GTCTGGCCCTTTTGGA G_(ks)T_(ks) ^(m)C_(ks)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)G_(ks)A_(e)  0  455 785909 1363 1378 10684 10699 GGTCTGGCCCTTTTGG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(ks)G_(e)  0  393 785922 2215 2230 11780 11795 GTTCTTGGACTCTCAA G_(ks)T_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(ks)A_(e) 37  695 785923 2216 2231 11781 11796 GGTTCTTGGACTCTCA G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(ks)A_(e)  0  706 785924 2217 2232 11782 11797 AGGTTCTTGGACTCTC A_(ks)G_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(e) 19  707 785925 2218 2233 11783 11798 CAGGTTCTTGGACTCT ^(m)C_(ks)A_(ks)G_(ks)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(ks)T_(e)  0  708 785938 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 71 1242

TABLE 22 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 (% SEQ Compound Start Stop Start Stop Sequence Inhi- ID Number Site Site Site Site (5′ to 3′) Chemistry Notation bition) NO 728708 1308 1323 10541 10556 AGCTTGGTCTTGACCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 12  436 728898 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 33  637 729049 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 55  718 729589 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(k)  0 1184 785372 1767 1782 11332 11347 TGTCACATCTCCACAT T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(es)T_(k) 16  635 785373 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 17  637 785383 2228 2243 11793 11808 ATTTCTGCTCCAGGTT A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks)T_(es)T_(k) 39  696 785384 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k)  0  718 785400 N/A N/A  9257  9272 TTCTGCAGGGAGTCAG T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k)  4 1255 785401 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k)  0 1184 785427 1767 1782 11332 11347 TGTCACATCTCCACAT T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(ks)T_(e)  0  635 785428 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(e)  0  637 785438 2228 2243 11793 11808 ATTTCTGCTCCAGGTT A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es)T_(ks)T_(e) 13  696 785439 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(ks)G_(e)  0  718 785455 N/A N/A  9257  9272 TTCTGCAGGGAGTCAG T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)A_(ks)G_(e)  0 1255 785456 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks)G_(es)A_(ks)G_(es)T_(ks) ^(m)C_(e)  0 1184 785472 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(es)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(es) ^(m)C_(es)A_(ks) ^(m)C_(k)  0  637 785478 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(es)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(es)A_(es)G_(ks)G_(k) 56  718 785488 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(es)G_(es)T_(ks) ^(m)C_(k) 14 1184 785515 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(e) 19  636 785516 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(e)  8  637 785525 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks)T_(e) 49  717 785526 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(e) 26  718 785543 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(e)  8 1256 785544 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(e)  0 1184 785559 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(es) ^(m)C_(es) ^(m)C_(es)A_(es) ^(m)C_(ks)A_(k) 11  636 785565 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(es) ^(m)C_(es)A_(es)G_(es)G_(ks)T_(k) 43  717 785574 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(es)A_(es)G_(es)T_(es) ^(m)C_(ks)A_(k)  0 1256 785612 1767 1782 11332 11347 TGTCACATCTCCACAT T_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(ks)T_(k)  0  635 785613 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) ^(m)C_(ks)A_(k)  0  636 785614 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(k) 29  637 785626 2228 2243 11793 11808 ATTTCTGCTCCAGGTT A_(ks)T_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es)T_(ks)T_(k)  6  696 785627 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(ks)T_(k)  0  717 785628 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(ks)G_(k)  0  718 785651 N/A N/A  9257  9272 TTCTGCAGGGAGTCAG T_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)A_(ks)G_(k)  0 1255 785652 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ks)A_(es)G_(ks)T_(es) ^(m)C_(ks)A_(k)  0 1256 785653 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks)G_(es)A_(ks)G_(es)T_(ks) ^(m)C_(k)  0 1184 785668 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(es) ^(m)C_(es)A_(es) ^(m)C_(ks)A_(k) 10  636 785674 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(es)A_(es)G_(es)G_(ks)T_(k) 44  717 785683 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(es)G_(es)T_(es) ^(m)C_(ks)A_(k)  0 1256 785698 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(ks) ^(m)C_(ds)A_(k)  6  636 785704 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ds)G_(ks)G_(ds)T_(k) 27  717 785713 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(ds)T_(ks) ^(m)C_(ds)A_(k)  0 1256 785740 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(k) 23  636 785741 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) ^(m)C_(k)  5  637 785750 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es)T_(k)  5  717 785751 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k)  9  718 785768 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)A_(k)  0 1256 785769 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k)  0 1184 785785 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(ks)A_(ds) ^(m)C_(k) 35  637 785791 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(ks)G_(ds)G_(k) 57  718 785801 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ks)A_(ds)G_(ks)T_(ds) ^(m)C_(k)  0 1184 785828 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)A_(k)  0  636 785829 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) ^(m)C_(k)  0  637 785838 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(es)T_(k) 24  717 785839 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k) 23  718 785856 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)A_(k)  0 1256 785857 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k)  0 1184 785873 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) ^(m)C_(e)  3  637 785879 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)G_(e) 43  718 785889 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(e)  1 1184 785916 1768 1783 11333 11348 CTGTCACATCTCCACA ^(m)C_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks)A_(e) 28  636 785917 1769 1784 11334 11349 GCTGTCACATCTCCAC G_(ks) ^(m)C_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 23  637 785926 2229 2244 11794 11809 TATTTCTGCTCCAGGT T_(ks)A_(ks)T_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(ks)T_(e) 45  717 785927 2230 2245 11795 11810 TTATTTCTGCTCCAGG T_(ks)T_(ks)A_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(ks)G_(e) 28  718 785938 N/A N/A  6548  6563 CCAATTTTGCATTCCA ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 75 1242 785944 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(ks)A_(e)  0 1256 785945 N/A N/A  9259  9274 CCTTCTGCAGGGAGTC ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(ks)T_(ks) ^(m)C_(e)  0 1184 786513 N/A N/A  9250  9265 GGGAGTCAGACCTACC G_(ks)G_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k)  0 1257 786514 N/A N/A  9252  9267 CAGGGAGTCAGACCTA ^(m)C_(ks)A_(ks)G_(ks)G_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)A_(k)  0 1258 786515 N/A N/A  9254  9269 TGCAGGGAGTCAGACC T_(ks)G_(ks) ^(m)C_(ks)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k)  0 1259 786516 N/A N/A  9256  9271 TCTGCAGGGAGTCAGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k)  0 1260 786517 N/A N/A  9257  9272 TTCTGCAGGGAGTCAG T_(ks)T_(ks) ^(m)C_(ks)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k)  0 1255 786518 N/A N/A  9258  9273 CTTCTGCAGGGAGTCA ^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k)  0 1256 786519 N/A N/A  9260  9275 GCCTTCTGCAGGGAGT G_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ds)A_(ks)G_(ks)T_(k)  0 1261 786520 N/A N/A  9261  9276 TGCCTTCTGCAGGGAG T_(ks)G_(ks) ^(m)C_(ks) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)G_(ks)A_(ks)G_(k)  0 1262 786521 N/A N/A  9262  9277 TTGCCTTCTGCAGGGA T_(ks)T_(ks)G_(ks) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks)G_(ks)A_(k)  0 1263 786522 N/A N/A  9264  9279 ATTTGCCTTCTGCAGG A_(ks)T_(ks)T_(ks)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k)  0 1264 786523 N/A N/A  9266  9281 TCATTTGCCTTCTGCA T_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k)  6 1265

TABLE 23 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ  Compound Start Stop Start Stop Sequence Chemistry (% ID Number Site Site Site Site (5′ to 3′) Notation Inhibition) NO 728466 427 442 8320 8335 GGTGTATTT G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 37 1254 CCCTGTC T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)G_(ks) T_(ks) ^(m)C_(k) 728708 1308 1323 10541 10556 AGCTTGGTC A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds) 37 436 TTGACCT G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 728998 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ks)A_(ds)A_(ds)G_(ds) 42 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) T_(ds) ^(m)C_(ks)A_(ks)A_(k) 729018 2172 2187 11737 11752 TCTGATATG T_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ds)T_(ds) 63 228 ATACCTA A_(ds)T_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)A_(k) 729454 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 56 995 GACGAGCA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds) G_(ks) ^(m)C_(ks)A_(k) 785376 2117 2132 11682 11697 GAAGTGAGT G_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)A_(ds) 44 207 CTCAAAC G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks) A_(es)A_(ks)A_(es) ^(m)C_(k) 785377 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 11 208 AGTCTCAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)A_(k) 785387 N/A N/A 5168 5183 GAGTGAGA G_(ks)A_(ds)G_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 18 1266 CGAGCAAA A_(ds) ^(m)C_(ds)G_(ds)A_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)A_(k) 785388 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ds)G_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 37 995 GACGAGCA A_(ds)G_(ds)A_(ds)C_(ds)G_(ks)A_(es) G_(ks) ^(m)C_(es)A_(k) 785431 2117 2132 11682 11697 GAAGTGAGT G_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)A 11 207 CTCAAAC _(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) A_(ks)A_(es)A_(ks) ^(m)C_(e) 785432 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)T 23 208 AGTCTCAA _(ds)G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(ks)A_(e) 785442 N/A N/A 5168 5183 GAGTGAGA G_(ks)A_(ds)G_(ds)T_(ds)G_(ds)A_(ds)G 6 1266 CGAGCAAA _(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ks)G_(es) ^(m) C_(ks)A_(es)A_(ks)A_(e) 785443 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ds)G_(ds)A_(ds)G_(ds)T_(ds)G 0 995 GACGAGCA _(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ks)G_(es)A_(ks) G_(es) ^(m)C_(ks)A_(e) 785474 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(es)G_(ks)A_(ds)A_(ds)G_(ds)T 43 208 AGTCTCAA _(ds)G_(ds)A_(ds)G_(ds)T_(ds)C_(ds)T_(es) ^(m)C_(es)A_(ks)A_(k) 785480 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(es)G_(ks)A_(ds)G_(ds)T_(ds) 22 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ds) A_(es)G_(es) ^(m)C_(ks)A_(k) 785519 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds) 55 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(es)A_(ks)A_(e) 785520 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds) 39 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) T_(ks)T_(es)A_(ks)A_(e) 785529 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 33 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds) G_(ks) ^(m)C_(es)A_(ks)A_(e) 785530 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 28 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ds) A_(ks)G_(es) ^(m)C_(ks)A_(e) 785561 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds) 34 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(es)T_(es) ^(m)C_(es)A_(es)A_(ks)A_(k) 785567 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 17 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(es)A_(es) G_(es) ^(m)C_(es)A_(ks)A_(k) 785618 2117 2132 11682 11697 GAAGTGAGT G_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 27 207 CTCAAAC A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(es) A_(ks)A_(es)A_(ks) ^(m)C_(k) 785619 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds) 36 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es) T_(ks)A_(es)A_(ks)A_(k) 785620 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds) 20 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(es) T_(ks) ^(m)C_(es)A_(ks)A_(k) 785632 N/A N/A 5168 5183 GAGTGAGA G_(ks)A_(ks)G_(ds)T_(ds)G_(ds)A_(ds) 17 1266 CGAGCAAA G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ks)G_(es) ^(m)C_(ks)A_(es)A_(ks)A_(k) 785633 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 38 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ks)A_(es) G_(ks) ^(m)C_(es)A_(ks)A_(k) 785634 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 35 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ks)G_(es) A_(ks)G_(es) ^(m)C_(ks)A_(k) 785670 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds) 32 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(es) ^(m)C_(es)A_(es)A_(ks)A_(k) 785676 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 25 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(es) G_(cs) ^(m)C_(es)A_(ks)A_(k) 785700 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds) 12 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ds)A_(ks)A_(ds)A_(k) 785706 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 16 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ks) G_(ds) ^(m)C_(ks)A_(ds)A_(k) 785744 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds) 25 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)A_(es)A_(k) 785745 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds) 42 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)T_(ks) T_(es) ^(m)C_(ks)A_(es)A_(k) 785754 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds) 27 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ks) G_(es) ^(m)C_(ks)A_(es)A_(k) 785755 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 36 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ks) A_(es)G_(ks) ^(m)C_(es)A_(k) 785787 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ks)A_(ds)A_(ds)G_(ds) 40 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks) T_(ds) ^(m)C_(ks)A_(ds)A_(k) 785793 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 37 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ks) A_(ds)G_(ks) ^(m)C_(ds)A_(k) 785832 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ks)A_(ds)G_(ds)T_(ds) 45 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)A_(es)A_(k) 785833 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ks)A_(ds)A_(ds)G_(ds) 24 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks) T_(es) ^(m)C_(ks)A_(es)A_(k) 785842 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ks)G_(ds)T_(ds)G_(ds) 5 1268 ACGAGCAA A_(ds)G_(ds)A_(dsni)C_(ds)G_(ds)A_(ks) G_(es) ^(m)C_(ks)A_(es)A_(k) 785843 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 24 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ks) A_(es)G_(ks) ^(m)C_(es)A_(k) 785875 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ks)A_(ds)A_(ds)G_(ds) 21 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) T_(ks) ^(m)C_(es)A_(ks)A_(e) 785881 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 42 995 GACGAGCA G_(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ds) A_(ks)G_(es) ^(m)C_(ks)A_(e) 785920 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ks)A_(ds)G_(ds)T_(ds) 49 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(ks)A_(ks)A_(e) 785921 2119 2134 11684 11699 AGGAAGTG A_(ks)G_(ks)G_(ks)A_(ds)A_(ds)G_(ds) 47 208 AGTCTCAA T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) T_(ks) ^(m)C_(ks)A_(ks)A_(e) 785930 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ks)G_(ds)T_(ds)G_(ds) 33 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds) G_(ks) ^(m)C_(ks)A_(ks)A_(e) 785931 N/A N/A 5170 5185 AGGAGTGA A_(ks)G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G 37 995 GACGAGCA _(ds)A_(ds)G_(ds)A_(ds)C_(ds)G_(ds)A_(k) _(s)G_(ks)T_(ks)A_(e) 785938 N/A N/A 6548 6563 CCAATTTTG ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds) 10 1242 CATTCCA T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 786501 2118 2133 11683 11698 GGAAGTGA G_(ks)G_(ks)A_(ks)A_(ds)G_(ds)T_(ds) 51 1267 GTCTCAAA G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ks)A_(ks)A_(k) 786502 2120 2135 11685 11700 GAGGAAGT G_(ks)A_(ks)G_(ks)G_(ds)A_(ds)A_(ds) 0 1269 GAGTCTCA G_(ds)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k) 786503 2171 2186 11736 11751 CTGATATGA ^(m)C_(ks)T_(ks)G_(ks)A_(ds)T_(ds)A_(ds) 59 1270 TACCTAA T_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)A_(ks)A_(k) 786504 2173 2188 11738 11753 ATCTGATAT A_(ks)T_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 36 1271 GATACCT T_(ds)A_(ds)T_(ds)G_(ds)A_(ds)T_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 786524 N/A N/A 5141 5156 ACGAGTTAT A_(ks) ^(m)C_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 74 1272 GGGAAGG T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds) A_(ds)A_(ks)G_(ks)G_(k) 786525 N/A N/A 5143 5158 GGACGAGTT G_(ks)G_(ks)A_(ks) ^(m)C_(ds)G_(ds)A_(ds) 37 1273 ATGGGAA G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds) G_(ds)G_(ks)A_(ks)A_(k) 786526 N/A N/A 5145 5160 TAGGACGA T_(ks)A_(ks)G_(ts)G_(ds)A_(ds) ^(m)C_(ds) 25 1274 GTTATGGG G_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds) T_(ds)G_(ks)G_(ks)G_(k) 786527 N/A N/A 5147 5162 AGTAGGAC A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)G_(ds) 0 1275 GAGTTATG A_(ds) ^(m)C_(ds)G_(ds)A_(ds)G_(ds)T_(ds) T_(ds)A_(ks)T_(ks)G_(k) 786528 N/A N/A 5149 5164 TGAGTAGGA T_(ks)G_(ks)A_(ks)G_(ds)T_(ds)A_(ds) 18 1276 CGAGTTA G_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds) G_(ds)T_(ks)T_(ks)A_(k) 786529 N/A N/A 5151 5166 GGTGAGTAG G_(ks)G_(ks)T_(ks)G_(ds)A_(ds)G_(ds) 48 1277 GACGAGT T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds) G_(ds)A_(ks)G_(ks)T_(k) 786530 N/A N/A 5153 5168 AGGGTGAGT A_(ks)G_(ks)G_(ks)G_(ds)T_(ds)G_(ds)A 19 1278 AGGACGA _(ds)G_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ks)G_(ks)A_(k) 786531 N/A N/A 5155 5170 AAAGGGTG A_(ks)A_(ks)A_(ks)G_(ds)G_(ds)G_(ds) 24 1279 AGTAGGAC T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) G_(ds)G_(ks)A_(ks) ^(m)C_(k) 786532 N/A N/A 5157 5172 GCAAAGGG G_(ks) ^(m)C_(ks)A_(ks)A_(ds)A_(ds)G_(ds) 24 1280 TGAGTAGG G_(ds)G_(ds)T_(ds)G_(ds)A_(ds)G_(ds) T_(ds)A_(ks)G_(ks)G_(k) 786533 N/A N/A 5159 5174 GAGCAAAG G_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)A_(ds) 0 1281 GGTGAGTA A_(ds)G_(ds)G_(ds)G_(ds)T_(ds)G_(ds) A_(ds)G_(ks)T_(ks)A_(k) 786534 N/A N/A 5161 5176 ACGAGCAA A_(ks) ^(m)C_(ks)G_(ks)A_(ds)G_(ds) 47 1282 AGGGTGAG ^(m)C_(ds)A_(ds)A_(ds)A_(ds)G_(ds) G_(ds)G_(ds)T_(ds)G_(ks)A_(ks)G_(k) 786535 N/A N/A 5163 5178 AGACGAGC A_(ks)G_(ks)A_(ks) ^(m)C_(ds)G_(ds)A_(ds) 35 1283 AAAGGGTG G_(ds)C_(ds)A_(ds)A_(ds)A_(ds)G_(ds) G_(ds)G_(ks)T_(ks)G_(k) 786536 N/A N/A 5164 5179 GAGACGAG G_(ks)A_(ks)G_(ks)A_(ds) ^(m)C_(ds)G_(ds) 40 1284 CAAAGGGT A_(ds)G_(ds)C_(ds)A_(ds)A_(ds)A_(ds) G_(ds)G_(ks)G_(ks)T_(k) 786537 N/A N/A 5165 5180 TGAGACGA T_(ks)G_(ks)A_(ks)G_(ds)A_(ds) ^(m)C_(ds) 22 1285 GCAAAGGG G_(ds)A_(ds)G_(ds)C_(ds)A_(ds)A_(ds) A_(ds)G_(ks)G_(ks)G_(k) 786538 N/A N/A 5166 5181 GTGAGACG G_(ks)T_(ks)G_(ks)A_(ds)G_(ds)A_(ds) 49 1286 AGCAAAGG ^(m)C_(ds)G_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds) A_(ds)A_(ks)G_(ks)G_(k) 786539 N/A N/A 5167 5182 AGTGAGAC A_(ks)G_(ks)T_(ks)G_(ds)A_(ds)G_(ds) 16 1287 GAGCAAAG A_(ds) ^(m)C_(ds)G_(ds)A_(ds)G_(ds) ^(m)C_(ds) A_(ds)A_(ks)A_(ks)G_(k) 786540 N/A N/A 5168 5183 GAGTGAGA G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds) 27 1266 CGAGCAAA G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)A_(k) 786541 N/A N/A 5169 5184 GGAGTGAG G_(ks)G_(ks)A_(ks)G_(ds)T_(ds)G_(ds) 37 1268 ACGAGCAA A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds) G_(ds) ^(m)C_(ks)A_(ks)A_(k) 786542 N/A N/A 5171 5186 TAGGAGTGA T_(ks)A_(ks)G_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 1 1288 GACGAGC G_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)G_(ds) A_(ks)G_(ks) ^(m)C_(k) 786543 N/A N/A 5172 5187 ATAGGAGTG A_(ks)T_(ks)A_(ks)G_(ds)G_(ds)A_(ds)G_(ds) 16 1289 AGACGAG T_(ds)G_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) G_(ks)A_(ks)G_(k) 786544 N/A N/A 5173 5188 AATAGGAGT A_(ks)A_(ks)T_(ks)A_(ds)G_(ds)G_(ds) 25 1290 GAGACGA A_(ds)G_(ds)T_(ds)G_(ds)A_(ds)G_(ds) A_(ds) ^(m)C_(ks)G_(ks)A_(k) 786545 N/A N/A 5174 5189 TAATAGGAG T_(ks)A_(ks)A_(ks)T_(ds)A_(ds)G_(ds) 12 1291 TGAGACG G_(ds)A_(ds)G_(ds)T_(ds)G_(ds)A_(ds) G_(ds)A_(ks) ^(m)C_(ks)G_(k) 786546 N/A N/A 5175 5190 GTAATAGGA G_(ks)T_(ks)A_(ks)A_(ds)T_(ds)A_(ds) 11 1292 GTGAGAC G_(ds)G_(ds)A_(ds)G_(ds)T_(ds)G_(ds) A_(ds)G_(ks)A_(ks) ^(m)C_(k) 786547 N/A N/A 5177 5192 GAGTAATAG G_(ks)A_(ks)G_(ks)T_(ds)A_(ds)A_(ds) 33 1293 GAGTGAG T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)G_(ds) T_(ds)G_(ks)A_(ks)G_(k) 786548 N/A N/A 5179 5194 ATGAGTAAT A_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 56 1294 AGGAGTG A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)G_(ds) A_(ds)G_(ks)T_(ks)G_(k) 786549 N/A N/A 5181 5196 TCATGAGTA T_(ks) ^(m)CC_(ks)A_(ks)T_(ds)G_(ds)A_(ds) 11 1295 ATAGGAG G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds) G_(ds)G_(ks)A_(ks)G_(k) 786550 N/A N/A 5183 5198 CCTCATGAG ^(m)C_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(ds)A_(ds) 0 1296 TAATAGG T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) A_(ds)T_(ds)A_(ks)G_(ks)G_(k)

TABLE 24 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID Compound NO: 1 NO: 1 NO: 2 NO: 2 SEQ Number Start  Stop Start Stop Sequence Chemistry % ID Site Site Site Site (5′ to 3′) Notation Inhibition NO 665892 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) G_(ds) ^(m)C_(ds)G_(ks)G_(ks)A_(k) 665893 1228 1243 10461 10476 GCACTGACA G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds) 0 39 CAGGCGG A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds) G_(ds)G_(ds) ^(m)C_(ks)G_(ks)G_(k) 728466 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 27 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 728489 484 499 8377 8392 AAGGGCACA A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds) 42 1249 GCGCAGG A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)G_(d) _(s) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 728670 1230 1245 10463 10478 TTGCACTGA T_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) 21 398 CACAGGC T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) A_(ds)G_(ks)G_(ks) ^(m)C_(k) 728707 1307 1322 10540 10555 GCTTGGTCTT G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds) 52 435 GACCTC T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 728708 1308 1323 10541 10556 AGCTTGGTC A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds) 40 436 TTGACCT G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 728958 1979 1994 11544 11559 CCTATACAG ^(m)C_(ks) ^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ds) 0 168 CTAGGCC ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ds) G_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 729037 2216 2231 11781 11796 GGTTCTTGG G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds) 68 706 ACTCTCA T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k) 729494 N/A N/A 6958 6973 GAATTTTGT G_(ks)A_(ks)A_(ks)T_(ds)T_(ds)T_(ds) 57 1065 GACTGTA T_(ds)G_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) T_(ds)G_(ks)T_(ks)A_(k) 729495 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 70 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(ks)T_(k) 785352 1225 1240 10458 10473 CTGACACAG ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) 0 1297 GCGGATG ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ds) G_(ks)G_(es)A_(ks)T_(es)G_(k) 785353 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ck)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks) ^(m)C_(es)G_(ks)G_(es)A_(k) 785396 N/A N/A 6979 6994 CATTCTATGC ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) 37 1298 CTTTTA A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) T_(es)T_(ks)T_(es)A_(k) 785397 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 0 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(es)T_(k) 785407 1225 1240 10458 10473 CTGACACAG ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) 0 1297 GCGGATG ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks) G_(es)G_(ks)A_(es)T_(ks)G_(e) 785408 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks) G_(es) ^(m)C_(ks)G_(es)G_(ks)A_(e) 785451 N/A N/A 6979 6994 CATTCTATGC ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) 13 1298 CTTTTA A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) T_(ks)T_(es)T_(ks)A_(e) 785452 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 10 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)G_(es)G_(ks)A_(k) 785461 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(es) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(es)G_(es)G_(ks)A_(k) 785486 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(es) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 51 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(es)T_(es)T_(ks)T_(k) 785496 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 0 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ds) G_(ks)G_(es)A_(ks)T_(e) 785497 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks)G_(es)G_(ks)A_(e) 785539 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) 61 1299 CCTTTT T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ks)T_(es)T_(ks)T_(e) 785540 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 51 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(es)T_(es)T_(ks)T_(k) 785548 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 0 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(es) ^(m)C_(es)G_(es)G_(es)A_(ks)T_(k) 785572 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks)T_(ks)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) 17 1299 CCTTTT _(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(es) ^(m)C_(es)T_(es)T_(es)T_(ks)T_(k) 785585 1225 1240 10458 10473 CTGACACAG ^(m)C_(ks)T_(ks)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) 0 1297 GCGGATG ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks)G_(es) G_(ks)A_(es)T_(ks)G_(k) 785586 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 0 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks) ^(m)C_(es)G_(ks)G_(es)A_(ks)T_(k) 785587 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ks) G_(es) ^(m)C_(ks)G_(es)G_(ks)A_(k) 785645 N/A N/A 6979 6994 CATTCTATGC ^(m)C_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) 56 1298 CTTTTA A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) T_(ks)T_(es)T_(ks)A_(k) 785646 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 3 1299 CCTTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(es)T_(ks)T_(k) 785647 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 0 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ks)C_(es) ^(m)C_(ks)T_(es)T_(ks)T_(k) 785657 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 0 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(es)G_(cs)G_(cs)A_(ks)T_(k) 785681 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 50 1299 CCTTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(es)T_(es)T_(es)T_(ks)T_(k) 785687 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 6 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks)G_(ds)G_(ks)A_(ds)T_(k) 785711 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) ^(m)C 46 1299 CCTTTT _(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ds)T_(ks)T_(ds)T_(k) 785721 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 0 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(k) _(s)G_(es)G_(ks)A_(cs)T_(k) 785722 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks) ^(m)C_(es)G_(ks)G_(es)A_(k) 785764 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 62 1299 CCTTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)T_(ks)T_(es)T_(k) 785765 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 40 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(es)T_(k) 785774 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) G_(ks) ^(m)C_(ds)G_(ks)G_(ds)A_(k) 785799 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 11 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ds)T_(ks)T_(ds)T_(k) 785809 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ds) ^(m)C_(ds) 0 397 GGCGGAT A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks)G_(es)G_(ks)A_(es)T_(k) 785810 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(k) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks) ^(m)C_(es)G_(ks)G_(es)A_(k) 785852 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) 44 1299 CCTTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)T_(ks)T_(es)T_(k) 785853 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds) 15 1066 GCCTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(es)T_(k) 785862 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 0 387 AGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) G_(ds) ^(m)C_(ks)G_(es)G_(ks)A_(e) 785887 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds) 49 1066 GCCTTT T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ds) G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) T_(ks)T_(e) 785897 1226 1241 10459 10474 ACTGACACA A_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ds) 0 397 GGCGGAT ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) G_(ds) ^(m)C_(ds)G_(ks)G_(ks)A_(ks)T_(e) 785898 1227 1242 10460 10475 CACTGACAC ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds) 0 387 AGGCGGA A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds) G_(ds)G_(ds) ^(m)C_(ks)G_(ks)G_(ks)A_(e) 785938 N/A N/A 6548 6563 CCAATTTTGC ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds) 0 1242 ATTCCA T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks) A_(e) 785940 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) 58 1299 CCTTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(ks)T_(ks) T_(e) 785941 N/A N/A 6981 6996 ACCATTCTAT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds) 59 1066 GCCTTT T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ds) G_(ds) ^(m)C_(ds) ^(m) _(p)TTTC_(ks)T_(ks) T_(ks)T_(e) 786551 N/A N/A 6979 6994 CATTCTATGC ^(m)C_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds) 24 1298 CTTTTA T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(ks) A_(k) 786552 N/A N/A 6980 6995 CCATTCTATG ^(m)C_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds) 43 1299 CCTTTT ^(m)C_(ds)T_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(ks) T_(k) 786553 N/A N/A 6982 6997 AACCATTCT A_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds) 33 1300 ATGCCTT T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) T_(k) 786554 N/A N/A 6983 6998 AAACCATTC A_(ks)A_(ks)A_(ks) ^(m)C_(ds) ^(m)C_(ds) 0 1301 TATGCCT A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks) T_(k) 786555 N/A N/A 6984 6999 TAAACCATT T_(ks)A_(ks)A_(ks)A_(ds) ^(m)C_(ds) 9 1302 CTATGCC ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) T_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 786556 N/A N/A 6985 7000 CTAAACCAT ^(m)C_(ks)T_(ks)A_(ks)A_(ds)A_(ds) 0 1303 TCTATGC ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(k) 786557 N/A N/A 6987 7002 CTCTAAACC ^(m)C_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ds) 0 1304 ATTCTAT A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) T_(ds)T_(ds) ^(m)C_(ds)T_(ks)A_(ks) T_(k) 786558 N/A N/A 6989 7004 TGCTCTAAA T_(ks)G_(ks) ^(m)C_(ks)T_(ds) ^(m)C_(ds) 0 1305 CCATTCT T_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) T_(k) 786559 N/A N/A 6991 7006 TTTGCTCTAA T_(ks)T_(ks)T_(ks)G_(ds) ^(m)C_(ds) 2 1306 ACCATT T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds) A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks) T_(ks)T_(k) 786560 N/A N/A 6994 7009 CTTTTTGCTC ^(m)C_(ks)T_(ks)T_(ks)T_(ds)T_(ds) 0 1307 TAAACC T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) T_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 786561 N/A N/A 6997 7012 AGACTTTTTG A_(ks)G_(ks)A_(ks) ^(m)C_(ds)T_(ds) 0 1308 CTCTAA T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks)A_(ks) A_(k) 786587 N/A N/A 6948 6963 ACTGTATTA A_(ks)C_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 22 1309 CCTATAC T_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds) A_(ds)T_(ks)A_(ks) ^(m)C_(k) 786588 N/A N/A 6949 6964 GACTGTATT G_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)T_(ds) 41 1310 ACCTATA A_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ds)A_(ks)T_(ks)A_(k) 786589 N/A N/A 6950 6965 TGACTGTATT T_(ks)G_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds) 18 1311 ACCTAT T_(ds)A_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m) C_(ds)T_(ks)A_(ks)T_(k) 786590 N/A N/A 6951 6966 GTGACTGTA G_(ks)T_(ks)G_(ks)A_(ds) ^(m)C_(ds)T_(ds) 62 1312 TTACCTA G_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)™ C_(ds) ^(m)C_(ks)T_(ks)A_(k) 786591 N/A N/A 6952 6967 TGTGACTGT T_(ks)G_(ks)T_(ks)G_(ds)A_(ds) ^(m)C_(ds) 81 1313 ATTACCT T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)T_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 786592 N/A N/A 6953 6968 TTGTGACTGT T_(ks)T_(ks)G_(ks)T_(ds)G_(ds)A_(ds) ^(m) 56 1314 ATTACC C_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) T_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 786593 N/A N/A 6954 6969 TTTGTGACTG T_(ks)T_(ks)T_(ks)G_(ds)T_(ds)G_(ds)A_(d) 50 1315 TATTAC _(s) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) T_(ks)A_(ks) ^(m)C_(k) 786594 N/A N/A 6955 6970 TTTTGTGACT T_(ks)T_(ks)T_(ks)T_(ds)G_(ds)T_(ds)G_(ds) 2 1316 GTATTA A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)A_(ds) T_(ks)T_(ks)A_(k) 786595 N/A N/A 6956 6971 ATTTTGTGAC A_(ks)T_(ks)T_(ks)T_(ds)T_(ds)G_(ds)T_(ds) 4 1317 TGTATT G_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) A_(ks)T_(ks)T_(k) 786596 N/A N/A 6957 6972 AATTTTGTG A_(ks)A_(ks)T_(ks)T_(ds)T_(ds)T_(ds)G_(ds) 0 1318 ACTGTAT T_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds) T_(ks)A_(ks)T_(k) 786597 N/A N/A 6959 6974 TGAATTTTGT T_(ks)G_(ks)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds) 64 1319 GACTGT T_(ds)G_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) T_(ks)G_(ks)T_(k) 786598 N/A N/A 6960 6975 TTGAATTTTG T_(ks)T_(ks)G_(ks)A_(ds)A_(ds)T_(ds)T_(ds) 45 1320 TGACTG T_(ds)T_(ds)G_(ds)T_(ds)G_(ds)A_(ds) C_(ks)T_(ks)G_(k) 786599 N/A N/A 6961 6976 GTTGAATTTT G_(ks)T_(ks)T_(ks)G_(ds)A_(ds)A_(ds)T_(ds) 0 1321 GTGACT T_(ds)T_(ds)T_(ds)G_(ds)T_(ds)G_(ds)A _(ks) ^(m)C_(ks)T_(k) 786600 N/A N/A 6962 6977 TGTTGAATTT T_(ks)G_(ks)T_(ks)T_(ds)G_(ds)A_(ds)A_(ds) 26 1322 TGTGAC T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)T_(ds)G_(ks) A_(ks) ^(m)C_(k)

TABLE 25 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop Sequence Chemistry % ID Number Site Site Site Site (5′ to 3′) Notation Inhibition NO 728466 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 12 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 728489 484 499 8377 8392 AAGGGCACAG A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C 0 1249 CGCAGG _(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds) G_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 728670 1230 1245 10463 10478 TTGCACTGAC T_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C 6 398 ACAGGC _(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m) C_(ds)A_(ds)G_(ks)G_(ks) ^(m)C_(k) 728708 1308 1323 10541 10556 AGCTTGGTCT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds) 11 436 TGACCT G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 729513 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds) 12 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks) A_(k) 785349 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 0 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) C_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 785398 N/A N/A 7314 7329 CAATGCAACA ^(m)C_(ks)A_(ds)A_(ds)T_(ds)G_(ds) ^(m) 0 1323 TCCATC C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)T_(es) ^(m)C_(k) 785399 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es) A_(k) 785404 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 0 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m) C_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(e) 785453 N/A N/A 7314 7329 CAATGCAACA ^(m)C_(ks)A_(ds)A_(ds)T_(ds)G_(ds) 0 1323 TCCATC ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(ks) ^(m)C_(e) 785454 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ks)A_(es)T_(ks) ^(m)C_(es) ^(m)C_(ks) A_(e) 785459 427 442 8320 8335 GGTGTATTTC G_(ks)G_(es)T_(ks)G_(ds)T_(ds)A_(ds) 5 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(es)G_(es)T_(ks) ^(m)C_(k) 785487 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ds)T_(es) ^(m)C_(es) ^(m)C_(ks)A_(k) 785493 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 0 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(e) 785494 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds) 21 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(e) 785541 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks) T_(e) 785542 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) A_(e) 785547 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 0 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(es) T_(es)G_(es)T_(es) ^(m)C_(ks)T_(k) 785573 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(es)T_(es) ^(m)C_(es) ^(m)C_(es)A_(ks) T_(k) 785581 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 0 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks) T_(es)G_(ks)T_(es) ^(m)C_(ks)T_(k) 785582 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds) 0 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m) C_(es)T_(ks)G_(es)T_(ks) ^(m)C_(k) 785648 N/A N/A 7314 7329 CAATGCAACA ^(m)C_(ks)A_(ks)A_(ds)T_(ds)G_(ds) ^(m) 0 1323 TCCATC C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(k) _(s) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(ks) ^(m)C_(k) 785649 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks) T_(k) 785650 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ks)A_(es)T_(ks) ^(m)C_(es) ^(m)C_(ks) A_(k) 785656 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 16 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(es)G_(es)T_(es) ^(m)C_(ks)T_(k) 785682 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ds)T_(es) ^(m)C_(es) ^(m)C_(es)A_(ks) T_(k) 785686 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 0 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(k) T_(ks)G_(ds)T_(ks) ^(m)C_(ds)T_(k) 785712 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(ks)A_(ds) T_(k) 785718 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) 0 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ks)G_(es)T_(ks) ^(m)C_(es)T_(k) 785719 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds) 26 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 785766 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) T_(k) 785767 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es) A_(k) 785772 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 1 1254 CCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ds)G_(ks)T_(ds) ^(m)C_(k) 785800 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ks)T_(ds) ^(m)C_(ks) ^(m)C_(ds) A_(k) 785806 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ks)T_(ds)A_(ds)T_(ds) 0 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ks)G_(es)T_(ks) ^(m)C_(es)T_(k) 785807 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 0 1254 CCTGTC T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) C_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 785854 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) T_(k) 785855 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es) A_(k) 785860 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 0 1254 CCTGTC T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) C_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(e) 785888 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) A_(e) 785894 426 441 8319 8334 GTGTATTTCC G_(ks)T_(ks)G_(ks)T_(ds)A_(ds)T_(ds) 30 1324 CTGTCT T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ds)G_(ks)T_(ks) ^(m)C_(ks)T_(e) 785895 427 442 8320 8335 GGTGTATTTC G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 0 1254 CCTGTC T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) C_(ds)T_(ks)G_(ks)T_(ks)C_(e) 785938 N/A N/A 6548 6563 CCAATTTTGC ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T 61 1242 ATTCCA _(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T _(ds)T_(k) ^(m)C_(ks) ^(m)C_(ks)A_(e) 785942 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds) 16 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds)C_(ds) A_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks) T_(e) 785943 N/A N/A 7316 7331 CCCAATGCAA ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds) 0 1097 CATCCA T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m) C_(ds)A_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks) A_(e) 786494 428 443 8321 8336 CGGTGTATTT ^(m)C_(ks)G_(ks)G_(ks)T_(ds)G_(ds)T_(d) 0 1326 CCCTGT _(s)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m) C_(ds) ^(m)C_(ds)T_(ks)G_(ks)T_(k) 786562 N/A N/A 7307 7322 ACATCCATCA A_(ks) ^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds) ^(m) 0 1327 ATGAGG C_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) T_(ds)G_(ds)A_(ks)G_(ks)G_(k) 786563 N/A N/A 7309 7324 CAACATCCAT ^(m)C_(ks)A_(ks)A_(ks) ^(m)C_(ds)A_(ds) 0 1328 CAATGA T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ks)G_(ks)A_(k) 786564 N/A N/A 7311 7326 TGCAACATCC T_(ks)G_(ks) ^(m)C_(ks)A_(ds)A_(ds) ^(m) 0 1329 ATCAAT C_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) A_(ds)T_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 786565 N/A N/A 7312 7327 ATGCAACATC A_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds)A_(ds) 0 1330 CATCAA ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) A_(ds)T_(ds) ^(m)C_(ks)AA_(ks)A_(k) 786566 N/A N/A 7313 7328 AATGCAACAT A_(ks)A_(ks)T_(ks)G_(ds) ^(m)C_(ds) 0 1331 CCATCA A_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m) C_(ks)A_(k) 786567 N/A N/A 7314 7329 CAATGCAACA ^(m)C_(ks)A_(ks)A_(ks)T_(ds)G_(ds) 0 1323 TCCATC ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds) T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks) T_(ks) ^(m)C_(k) 786568 N/A N/A 7315 7330 CCAATGCAAC ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds) 0 1325 ATCCAT G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks) T_(k) 786569 N/A N/A 7317 7332 ACCCAATGCA A_(ks) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds) 33 1332 ACATCC A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 786570 N/A N/A 7318 7333 TACCCAATGC T_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ds) 0 1333 AACATC A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) A_(ds) ^(m)C_(ds)A_(ks)T_(ks) ^(m)C_(k) 786571 N/A N/A 7319 7334 ATACCCAATG A_(ks)T_(ks)A_(ks) ^(m)C_(ds) ^(m)C_(ds) 1 1334 CAACAT ^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ks)A_(ks)T_(k) 

TABLE 26 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop Sequence Chemistry % ID Number Site Site Site Site (5′ to 3′) Notation Inhibition NO 665892 1227 1242 10460 10475 CACTGACA ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds) 0 387 CAGGCGGA ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds) G_(ds) ^(m)C_(ds)G_(ks)G_(ks)A_(k) 665893 1228 1243 10461 10476 GCACTGAC G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds) 0 39 ACAGGCGG A_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds) G_(ds)G_(ds) ^(m)C_(ks)G_(ks)G_(k) 666168 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m) 11 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ds)T_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 728458 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ks)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 728466 427 442 8320 8335 GGTGTATTT G_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds) 37 1254 CCCTGTC T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 728489 484 499 8377 8392 AAGGGCAC A_(ks)A_(ks)G_(ks)G_(ds)G_(ds) ^(m)C_(ds) 2 1249 AGCGCAGG A_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds) G_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 728670 1230 1245 10463 10478 TTGCACTGA T_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) 0 398 CACAGGC T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) ^(m) C_(ds)A_(ds)G_(ks)G_(ks) ^(m)C_(k) 728707 1307 1322 10540 10555 GCTTGGTCT G_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds) 0 435 TGACCTC T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 728708 1308 1323 10541 10556 AGCTTGGTC A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds) 41 436 TTGACCT G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 728958 1979 1994 11544 11559 CCTATACA ^(m)C_(ks) ^(m)C_(ks)T_(ks)A_(ds)T_(ds)A 0 168 GCTAGGCC _(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds) A_(ds)G_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 728996 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 9 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(k) 729037 2216 2231 11781 11796 GGTTCTTGG G_(ks)G_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds) 47 706 ACTCTCA T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k) 785347 390 405 4715 4730 ATGGTGTTA A_(ks)T_(ds)G_(ds)G_(ds)T_(ds)G_(ds) 0 122 TCTCCGT T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)G_(es)T_(k) 785348 392 407 4717 4732 AGATGGTG A_(ks)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ks) ^(m) C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 785374 2112 2127 11677 11692 GAGTCTCA G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 0 205 AACCAGGG ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m) C_(ks)A_(es)G_(ks)G_(es)G_(k) 785375 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 0 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A _(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 785390 N/A N/A 5284 5299 CACCACTGT ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 0 938 GTACCCC ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)T_(ds) A_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 785391 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ks)T_(es)A_(ks) ^(m)C_(es)T_(k) 785402 390 405 4715 4730 ATGGTGTTA A_(ks)T_(ds)G_(ds)G_(ds)T_(ds)G_(ds) 0 122 TCTCCGT T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)G_(ks)T_(e) 785403 392 407 4717 4732 AGATGGTG A_(ks)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 785429 2112 2127 11677 11692 GAGTCTCA G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 6 205 AACCAGGG ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(ks)G_(e) 785430 2114 2129 11679 11694 GTGAGTCTC G_(ls)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 0 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ks)A _(es) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(e) 785445 N/A N/A 5284 5299 CACCACTGT ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 0 938 GTACCCC ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)T_(ks) A_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(e) 785446 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ks) G_(es)T_(ks)A_(es)T_(ks) ^(m)C_(e) 785458 392 407 4717 4732 AGATGGTG A_(ks)G_(es)A_(ks)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 785473 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(es)G_(ks)A_(ds)G_(ds)T_(ds) 22 206 AAACCAG ^(m)C_(ds)T_(ds)C_(ds)A_(ds)A_(ds) A_(ds) ^(m)C_(es) ^(m)C_(es)A_(ks)G_(k) 785482 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(es) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ds)T_(es)A_(es) ^(m)C_(ks) ^(m)C_(k) 785491 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds) T_(ks) ^(m)C_(es) ^(m)C_(ks)G_(e) 785492 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ds)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 785517 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 7 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C _(ds) ^(m)C_(ks)A_(es)G_(ks)G_(e) 785518 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 31 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A _(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(e) 785533 N/A N/A 5285 5300 TCACCACTG T_(ks)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) T_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(e) 785534 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ds)T_(ks)A_(es) ^(m)C_(ks) ^(m)C_(e) 785546 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(es) ^(m)C_(es) T_(es) ^(m)C_(es) ^(m)C_(ks)G_(k) 785560 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(es) ^(m)C_(es) ^(m)C_(es)A_(es)G_(ks)G_(k) 785569 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(es) T_(es)A_(es) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(k) 785578 390 405 4715 4730 ATGGTGTTA A_(ks)T_(ks)G_(ds)G_(ds)T_(ds)G_(ds) 0 122 TCTCCGT T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)G_(ks)T_(k) 785579 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(es) T_(ks) ^(m)C_(es) ^(m)C_(ks)G_(k) 785580 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ds)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(ks)C_(k) 785615 2112 2127 11677 11692 GAGTCTCA G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 0 205 AACCAGGG ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(ks)G_(k) 785616 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(ks)G_(k) 785617 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 9 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ks) A_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(k) 785637 N/A N/A 5284 5299 CACCACTGT ^(m)C_(ks)A_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 0 938 GTACCCC ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)T_(ks) A_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(k) 785638 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ks) T_(es)A_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(k) 785639 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ks) G_(es)T_(ks)A_(es) ^(m)C_(ks) ^(m)C_(k) 785655 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(es) T_(es) ^(m)C_(es) ^(m)C_(ks)G_(k) 785669 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C _(es) ^(m)C_(es)A_(es)G_(ks)G_(k) 785678 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) T_(es)A_(es) ^(m)C_(es) ^(m)C_(ks)C_(k) 785685 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks) T_(ds) ^(m)C_(ks) ^(m)C_(ds)G_(k) 785699 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(ks)G_(ds)G_(k) 785708 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) T_(ks)A_(ds) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(k) 785716 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks) T_(es) ^(m)C_(ks) ^(m)C_(es)G_(k) 785717 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ds)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 785742 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C _(ks) ^(m)C_(es)A_(ks)G_(es)G_(k) 785743 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 0 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A _(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 785758 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) T_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 785759 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(dsni)C_(ds)T_(ds)G_(ds)T_(ds) G_(ks)T_(es)A_(ks)T_(es)T_(k) 785771 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ks)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(k) 785786 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 0 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) A_(ks) ^(m)C_(ds) ^(m)C_(ks)A_(ds)G_(k) 785795 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ks)T_(ds)A_(ks) ^(m)C_(ds) ^(m)C_(k) 785804 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ks)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks) T_(es) ^(m)C_(ks) ^(m)C_(es)G_(k) 785805 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ks)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 785830 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k) 785831 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 0 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) A_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 785846 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds) ^(m)C_(ds) 0 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) T_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 785847 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ks)T_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 785859 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ks)T_(ds)G_(ds)G_(ds) 8 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 785874 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 0 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(e) 785883 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m) 0 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ds)T_(ks)A_(es) ^(m)C_(ks) ^(m)C_(e) 785892 391 406 4716 4731 GATGGTGTT G_(ks)A_(ks)T_(ks)G_(ds)G_(ds)T_(ds) 0 1335 ATCTCCG G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds) T_(ks) ^(m)C_(ks) ^(m)C_(ks)G_(e) 785893 392 407 4717 4732 AGATGGTG A_(ks)G_(ks)A_(ks)T_(ds)G_(ds)G_(ds) 0 123 TTATCTCC T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) C_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 785918 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds) 0 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(ks)G_(e) 785919 2114 2129 11679 11694 GTGAGTCTC G_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds) 44 206 AAACCAG ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)G_(e) 785934 N/A N/A 5285 5300 TCACCACTG T_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds) ^(m)C_(ds) 21 939 TGTACCC A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) T_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(e) 785935 N/A N/A 5286 5301 ATCACCACT A_(ks)T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) ^(m) 19 927 GTGTACC C_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) G_(ds)T_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 785938 N/A N/A 6548 6563 CCAATTTTG ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds) 68 1242 CATTCCA T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 786493 393 408 4718 4733 AAGATGGT A_(ks)A_(ks)G_(ks)A_(ds)T_(ds)G_(ds) 0 1337 GTTATCTC G_(ds)T_(ds)G_(ds)T_(ds)T_(ds)A_(ds) T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 786499 2113 2128 11678 11693 TGAGTCTCA T_(ks)G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds) 16 1336 AACCAGG T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 786500 2115 2130 11680 11695 AGTGAGTC A_(ks)G_(ks)T_(ks)G_(ds)A_(ds)G_(ds) 0 1338 TCAAACCA T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) A_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k)

TABLE 27 Inhibition of IRF5 mRNA by modified oligonucleotides targeting SEQ ID NO: 1 and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start Stop Sequence Chemistry % ID Number Site Site Site Site (5′ to 3′) Notation Inhibition NO 728806 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 32 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) T_(ds)T_(ks)T_(ks)G_(k) 729205 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T 75 937 ACCCCA _(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 729433 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 60 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)C_(ds) A_(ds)T_(ks)G_(ks)G_(k) 785368 1558 1573 11123 11138 GTCTTTGAGG G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 0 537 TCTGGG A_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es) G_(ks)G_(es)G_(k) 785369 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 68 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 785385 N/A N/A 4365 4380 GTCTAGTGTC G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds) 42 1339 ATGGAA T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ks) G_(es)G_(ks)A_(es)A_(k) 785386 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 44 974 CATGG G_(ds)T_(ds)G_(ds)T_(ds)C_(ks)A_(es) T_(ks)G_(es)G_(k) 785389 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) 43 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 785423 1558 1573 11123 11138 GTCTTTGAGG G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 33 537 TCTGGG A_(ds)G_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks) G_(es)G_(ks)G_(e) 785424 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 40 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ks)G_(es)T_(ks) ^(m)C_(es)T_(ks)G_(e) 785440 N/A N/A 4365 4380 GTCTAGTGTC G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds) 35 1339 ATGGAA T_(ds)G_(ds)T_(ds)T_(ds)A_(ks)T_(es) G_(ks)G_(es)A_(ks)A_(e) 785441 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 8 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ks) ^(m)C_(es) A_(ks)T_(es)G_(ks)G_(e) 785444 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) 40 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 785470 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(es)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 49 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) T_(es) ^(m)C_(es)T_(ks)G_(k) 785479 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(es)G_(ks)T_(ds)T_(ds)T_(ds)A 55 974 CATGG _(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(es) T_(es)G_(ks)G_(k) 785481 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(es) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T 63 937 ACCCCA _(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) C_(ds) ^(m)C_(es) ^(m)C_(es) ^(m)C_(ks)A_(k) 785511 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 67 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(e) 785512 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 43 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) T_(ks) ^(m)C_(es)T_(ks)G_(e) 785527 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 44 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) T_(ks)G_(es)G_(ks)A_(e) 785528 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)A 38 974 CATGG _(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(k) _(s)T_(es)G_(ks)G_(e) 785531 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds) 19 936 CCCCAT T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)T_(e) 785532 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) 66 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 785557 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 56 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(es)T_(es) ^(m)C_(es)T_(es)G_(ks)G_(k) 785566 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 54 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(es)A_(es) T_(es)G_(es)G_(ks)A_(k) 785568 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds) 44 936 CCCCAT G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es)A_(ks)T_(k) 785606 1558 1573 11123 11138 GTCTTTGAGG G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) 34 537 TCTGGG G_(ds)A_(ds)G_(ds)G_(ds)T_(ks)C_(es)T_(ks) G_(es)G_(ks)G_(k) 785607 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 52 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(es)G_(ks)G_(k) 785608 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 33 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ks)G_(es) T_(ks) ^(m)C_(es)T_(ks)G_(k) 785629 N/A N/A 4365 4380 GTCTAGTGTC G_(ks)T_(ks) ^(m)C_(ds)T_(ds)A_(ds)G_(ds) 9 1339 ATGGAA T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(es) G_(ks)G_(es)A_(ks)A_(k) 785630 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 10 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(es) T_(ks)G_(es)G_(ks)A_(k) 785631 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 0 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ks) ^(m)C_(es) A_(ks)T_(es)G_(ks)G_(k) 785635 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds) 0 936 CCCCAT G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m) C_(ks) ^(m)C_(es) ^(m)C_(ks)C_(es)A_(ks) T_(k) 785636 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T 15 937 ACCCCA _(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ks) ^(m) C_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(k) 785666 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 74 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(es) ^(m)C_(es)T_(es)G_(ks)G_(k) 785675 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 60 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(es) T_(es)G_(es)G_(ks)A_(k) 785677 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)G 64 936 CCCCAT _(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m) C_(es) ^(m)C_(es) ^(m)C_(es)A_(ks)T_(k) 785696 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 56 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ks) ^(m)C_(ds)T_(ks)G_(ds)G_(k) 785705 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 40 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ks) T_(ds)G_(ks)G_(ds)A_(k) 785707 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds) 54 936 CCCCAT G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ks)A_(ds)T_(k) 785736 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 54 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ks) ^(m) C_(es)T_(ks)G_(es)G_(k) 785737 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 44 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ks) T_(es) ^(m)C_(ks)T_(es)G_(k) 785752 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 44 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ks) T_(es)G_(ks)G_(es)A_(k) 785753 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 24 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ks) A_(es)T_(ks)G_(es)G_(k) 785756 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds) 42 936 CCCCAT G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(k) 785757 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds) 17 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 785783 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 57 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ks) T_(ds) ^(m)C_(ks)T_(ds)G_(k) 785792 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 36 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ks) A_(ds)T_(ks)G_(ds)G_(k) 785794 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) 40 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(k) 785824 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds) 46 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k) 785825 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ks)T_(ds) ^(m)C_(ds) 56 539 GGTCTG T_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds) G_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 785840 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)A_(ds) 57 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ks) T_(es)G_(ks)G_(es)A_(k) 785841 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ks)T_(ds)T_(ds)T_(ds) 16 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ks) A_(es)T_(ks)G_(es)G_(k) 785844 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds)G 10 936 CCCCAT _(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C _(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(k) 785845 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) 6 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 785871 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 38 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) T_(ks) ^(m)C_(es)T_(ks)G_(e) 785880 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 39 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) A_(ks)T_(es)G_(ks)G_(e) 785882 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) 39 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 785912 1559 1574 11124 11139 GGTCTTTGAG G_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds) 33 538 GTCTGG T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(ks)G_(e) 785913 1560 1575 11125 11140 CGGTCTTTGA ^(m)C_(ks)G_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 32 539 GGTCTG T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) T_(ks) ^(m)C_(ks)T_(ks)G_(e) 785928 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)A_(ds) 39 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) T_(ks)G_(ks)G_(ks)A_(e) 785929 N/A N/A 4367 4382 TTGTCTAGTGT T_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds) 20 974 CATGG A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) A_(ks)T_(ks)G_(ks)G_(e) 785932 N/A N/A 5282 5297 CCACTGTGTA ^(m)C_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)T_(ds) 57 936 CCCCAT G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)T_(e) 785933 N/A N/A 5283 5298 ACCACTGTGT A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds) 47 937 ACCCCA T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 785938 N/A N/A 6548 6563 CCAATTTTGC ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)T_(ds)T_(ds) 75 1242 ATTCCA T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 786572 N/A N/A 4358 4373 GTCATGGAAT G_(ks)T_(ks) ^(m)C_(ks)A_(ds)T_(ds)G_(ds) 54 1341 TTTGTG G_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ds) T_(ds)G_(ks)T_(ks)G_(k) 786573 N/A N/A 4360 4375 GTGTCATGGA G_(ks)T_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds) 58 1342 ATTTTG T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)T_(ds) T_(ds)T_(ks)T_(ks)G_(k) 786574 N/A N/A 4362 4377 TAGTGTCATG T_(ks)A_(ks)G_(ks)T_(ds)G_(ds)T_(ds) 38 1343 GAATTT ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds) A_(ds)T_(ks)T_(ks)T_(k) 786575 N/A N/A 4363 4378 CTAGTGTCAT ^(m)C_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ds) 34 1344 GGAATT T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) A_(ds)A_(ks)T_(ks)T_(k) 786576 N/A N/A 4364 4379 TCTAGTGTCAT T_(ks) ^(m)C_(ks)T_(ks)A_(ds)G_(ds)T_(ds) 14 1345 GGAAT G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) G_(ds)A_(ks)A_(ks)T_(k) 786577 N/A N/A 4365 4380 GTCTAGTGTC G_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ds)G_(ds) 38 1339 ATGGAA T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds) G_(ds)G_(ks)A_(ks)A_(k) 786578 N/A N/A 4366 4381 TGTCTAGTGTC T_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)A_(ds) 61 1340 ATGGA G_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) T_(ds)G_(ks)G_(ks)A_(k) 786579 N/A N/A 4368 4383 CTTGTCTAGTG ^(m)C_(ks)T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds) 58 1346 TCATG T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m) C_(ds)A_(ks)T_(ks)G_(k) 786580 N/A N/A 4369 4384 TCTTGTCTAGT T_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)T_(ds) 0 1347 GTCAT ^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) T_(ds) ^(m)C_(ks)A_(ks)T_(k) 786581 N/A N/A 4370 4385 TTCTTGTCTAG T_(ks)T_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds) 49 1348 TGTCA T_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds) G_(ds)T_(ks) ^(m)C_(ks)A_(k) 786582 N/A N/A 4371 4386 TTTCTTGTCTA T_(ks)T_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds) 53 1349 GTGTC G_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds) T_(ds)G_(ks)T_(ks) ^(m)C_(k) 786583 N/A N/A 4372 4387 CTTTCTTGTCT ^(m)C_(ks)T_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds) 48 1350 AGTGT T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) G_(ds)T_(ks)G_(ks)T_(k) 786584 N/A N/A 4374 4389 AGCTTTCTTGT A_(ks)G_(ks) ^(m)C_(ks)T_(ds)T_(ds)T_(ds) 20 1351 CTAGT ^(m)C_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) T_(ds)A_(ks)G_(ks)T_(k) 786585 N/A N/A 4376 4391 TCAGCTTTCTT T_(ks) ^(m)C_(ks)A_(ks)G_(ds) ^(m)C_(ds)T_(ds) 15 1352 GTCTA T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds) T_(ds) ^(m)C_(ks)T_(ks)A_(k) 786586 N/A N/A 4378 4393 CATCAGCTTTC ^(m)C_(ks)A_(ks)T_(ks) ^(m)C_(ds)A_(ds)G_(ds) 28 1353 TTGTC ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) T_(ds)G_(ks)T_(ks) ^(m)C_(k)

Example 3: Dose-Dependent Inhibition of Human IRF5 by cEt Gapmers

Modified oligonucleotides described in the studies above exhibiting significant in vitro inhibition of IRF5 RNA were selected and tested at various doses in THP-1 cells, as well as in KARPAS-229 cells. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

Assay in THP-1 cells

Cultured THP-1 cells at a density of 30,000 cells per well were transfected using electroporation with modified oligonucleotides diluted to different concentrations as specified in the Tables below. After a treatment period of approximately 24 hours, IRF5 RNA levels were measured as previously described using the human IRF5 primer-probe set HTS4167. IRF5 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent inhibition of IRF5, relative to untreated control cells. The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide is also presented. IC₅₀ was calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 28 Multi-dose assay of modified oligonucleotides in THP-1 cells % Inhibition Compound 185.19 555.56 1666.67 5000.00 IC₅₀ No. nM nM nM nM (μM) 665795 36 57 76 85 0.4 665892 40 59 74 82 0.3 665893 26 53 74 83 0.6 665908 19 45 57 73 1.1 665933 30 38 66 79 0.8 728408 19 32 55 82 1.1 728458 29 45 58 80 0.8 728498 24 31 61 81 1.0 728670 58 51 70 79 0.1 728673 25 32 51 84 1.1 728695 23 54 72 80 0.6 728696 38 62 73 89 0.3 728705 39 57 71 82 0.4 728706 35 55 72 92 0.4 728707 50 64 74 85 0.2 728708 53 69 86 88 0.1 728806 33 47 74 87 0.5

TABLE 29 Multi-dose assay of modified oligonucleotides in THP-1 cells % Inhibition Compound 185.19 555.5556 185.19 5000.0 IC₅₀ No. nM nM nM nM (μM) 665893 25 50 64 81 0.7 665933 18 30 67 69 1.2 728739 14 26 55 58 2.2 728741 13 35 65 82 1.0 728759 40 49 49 68 0.8 728778 10 32 46 79 1.5 728793 10 21 39 68 2.4 728800 23 39 62 68 1.1 728802 20 35 34 65 2.5 728887  8 34 60 72 1.4 728891 43 23 50 74 1.2 728893  9 28 45 74 1.7 728894 20 42 68 85 0.8 728898 16 41 69 86 0.8 728899 10 34 65 79 1.1 728905 21 31 57 77 1.2 728944 15 21 71 79 1.1 728954  7 21 60 82 1.3 728970 30 50 78 85 0.5

TABLE 30 Multi-dose assay of modified oligonucleotides in THP-1 cells % Inhibition Compound 185.19 555.56 185.19 5000.0 IC₅₀ No. nM nM nM nM (μM) 665893 38 59 72 83 0.4 665933 13 39 52 71 1.4 666168 29 30 60 82 0.9 728958 30 43 68 83 0.7 728969 30 55 81 89 0.5 728996 36 57 73 84 0.4 728998 27 56 73 85 0.5 729018 33 52 69 85 0.5 729037 58 64 86 94 0.1 729038 41 65 89 92 0.3 729039 40 50 77 90  0.39 729049 35 57 76 85 0.4 729050 21 52 75 90 0.6 729205 23 42 73 84 0.7 729206 11 40 54 73 1.3 729433 25 41 65 86 0.8 729453 16 43 61 80 1.0 729454 31 40 69 87 0.7 729456 11 38 63 80 1.1

Multi-dose assay of modified oligonucleotides in THP-1 cells % Inhibition Compound 185.19 555.56 185.19 5000.0 IC₅₀ No. nM nM nM nM (μM) 665893 24 53 74 86 0.6 665933 13 36 58 71 1.3 666168 29 46 65 82 0.7 728958  0 24 50 73 1.8 728969 18 35 49 73 1.4 728996 12 34 60 84 1.1 728998 19 47 70 85 0.7 729018  5 31 53 73 1.5 729037  5 34 54 77 1.4 729038  0 0 10 53 >5.0  729039 18 31 63 81 1.1 729049 22 39 57 80 1.0 729050 42 63 85 91 0.3 729205 27 42 67 80 0.8 729206 16 57 74 86 0.6 729433  0 35 48 72 1.7 729453 18 41 67 89 0.8 729454 14 47 70 85 0.8 729456  3 32 60 85 1.2

Assay in KARPAS-229 Cells

Cultured KARPAS-229 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to different concentrations as specified in the Tables below. After a treatment period of approximately 24 hours, IRF5 mRNA levels were measured as previously described using the Human IRF5 primer-probe set RTS4524. IRF5 mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent inhibition of IRF5, relative to untreated control cells.

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide is also presented. IC₅₀ was calculated using a linear regression on a log/linear plot of the data in excel. ‘N.D.’ indicates that the % inhibition is not defined for that dosage with the modified oligonucleotide.

TABLE 32 Multi-dose assay of modified oligonucleotides in KARPAS-229 cells % Inhibition Compound 444.44 1333.33 4000.00 12000.00 IC₅₀ No. nM nM nM nM (μM) 728466 32 38 56 69 2.6 729037 52 65 79 86 0.3 729476 38 66 78 83 0.7 785350 23 40 62 87 2.0 785475 31 44 66 81 1.6 785477 34 48 62 74 1.6 785478 53 69 80 86 0.3 785485 42 68 78 82 0.5 785502 38 47 69 78 1.2 785522 39 59 73 84 0.8 785537 47 66 75 82 0.4 785563 25 51 64 77 1.8 785583 15 32 66 76 2.7 785661 22 32 41 58 7.0 785672 46 64 73 84 0.5 785791 42 62 67 79 0.7 785876 41 56 67 81 0.9 785938 61 79 84 88 0.1 786507 51 74 83 89 0.3

TABLE 33 Multi-dose assay of modified oligonucleotides in KARPAS-229 cells % Inhibition Compound 444.44 1333.33 4000.00 12000.00 IC₅₀ No. nM nM nM nM (μM) 729018 59 68 78 83 0.1 729049 51 66 77 84 0.3 729454 12 41 58 70 3.0 729495 44 60 74 86 0.7 785519  6 12 49 65 5.5 785525 40 53 71 79 1.0 785674 57 71 77 83 0.1 785764 29 N.D 61 81 1.8 785920 21 13 71 76 2.9 785926 46 52 67 74 0.8 785938 54 75 87 91 0.2 786501 27 39 68 79 1.9 786503 42 45 76 77 1.0 786524 50 54 73 81 0.6 786538 60 49 74 77 0.3 786548 15 46 52 70 3.0 786590  9 39 70 81 2.3 786591 38 44 66 78 1.4 786597 32 59 70 81 1.1

TABLE 34 Multi-dose assay of modified oligonucleotides in KARPAS-229 cells % Inhibition Compound 444.44 1333.33 4000.00 12000.00 IC₅₀ No. nM nM nM nM (μM) 728466 25 56 50 67 2.4 728708 33 41 46 55 6.1 729037 54 72 75 82 0.2 729205 16 41 57 65 3.3 729433 37 N.D. 70 84 1.1 729494 41 66 67 78 0.7 785369 31 29 46 57 6.5 785481 28 45 62 77 1.9 785511 39 43 63 72 1.6 785532 26 38 56 70 2.7 785539 37 45 62 73 1.6 785666 22 58 69 79 1.5 785675 33 50 57 70 1.9 785677 14 39 55 71 3.1 785919 23 39 50 59 4.4 785938 62 82 87 88 <0.4 785940 31 44 70 78 1.6 785941 33 56 61 75 1.3 786578  0 42 65 74 3.3

Example 4: Tolerability of Modified Oligonucleotides Targeting Human IRF5 in CD-1 Mice

CD-1 mice are a multipurpose mouse model frequently utilized for safety and efficacy testing. The mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Study 1 Treatment

Groups of 6- to 8-week-old male CD-1 mice were injected subcutaneously once a week for seven weeks (for a total of 7 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized 48 hours following the final administration.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the Table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 35 Plasma chemistry markers in male CD-1 mice Compound BUN Albumin AST ALT TBIL No. (mg/dL) (g/dL) (IU/L) (IU/L) (mg/dL) PBS 25 3.5 57 45 0.2 665795 27 3.2 237 541 0.3 665892 35 3.3 212 245 0.2 665893 25 3.5 210 290 0.2 665908 29 4.1 4665 6042 0.5 665933 31 3.8 767 1353 0.3 666168 26 3.4 3931 3855 0.7 666178 30 2.9 16490 14669 6.4 728458 32 3.7 821 1311 0.2 728706 28 3.7 2893 3673 0.8 728708 24 3.9 1770 3270 0.2 728759 22 3.7 860 599 0.2 728806 38 3.8 2503 2422 0.4 728958 23 3.0 214 158 0.2 728969 22 3.5 70 59 0.2 728970 20 3.6 157 140 0.2 728998 24 3.5 583 865 0.2 729018 19 3.2 86 66 0.2 729049 21 3.7 425 771 0.2 729050 22 3.5 193 246 0.2 729213 25 3.1 344 411 0.2 729433 26 3.7 802 791 0.2 729454 25 3.6 3958 4541 0.5 729476 77 2.7 1660 2046 0.7 729494 20 3.2 157 149 0.2 729495 57 3.2 240 254 0.1 729513 23 4.8 1558 2743 0.4

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 44, and the average body weight for each group is presented in the Table below. Heart, kidney, spleen, liver and thymus weights were measured at the end of the study and are presented in the Table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 36 Body and organ weights (in grams) Compound Body Weight (g) Heart Kidney Spleen Liver Thymus No. Day 1 Day 44 (g) (g) (g) (g) (g) PBS 34 37 0.2 0.7 0.1 2.2 0.05 665795 34 40 0.2 0.7 0.2 2.6 0.03 665892 34 38 0.2 0.8 0.2 2.9 0.02 665893 34 39 0.2 0.8 0.2 2.6 0.02 665908 34 35 0.2 0.6 0.2 3.5 0.02 665933 34 39 0.2 0.7 0.1 3.1 0.02 666168 34 31 0.2 0.4 0.2 2.3 0.01 666178 33 28 0.1 0.6 0.1 1.8 0.02 728458 34 37 0.2 0.8 0.2 3.3 0.05 728706 34 31 0.2 0.6 0.1 2.3 0.01 728708 33 36 0.2 0.7 0.2 3.0 0.03 728759 33 39 0.2 0.7 0.1 3.5 0.04 728806 33 33 0.1 0.6 0.1 3.0 0.02 728958 34 39 0.2 0.8 0.2 2.8 0.03 728969 34 38 0.2 0.6 0.1 2.2 0.05 728970 32 37 0.2 0.6 0.1 2.3 0.04 728998 34 41 0.2 0.7 0.2 3.2 0.05 729018 34 37 0.2 0.7 0.1 2.2 0.04 729049 34 36 0.2 0.6 0.2 2.6 0.02 729050 34 36 0.2 0.6 0.1 2.4 0.04 729213 33 35 0.2 0.7 0.1 2.0 0.01 729433 32 32 0.1 0.6 0.1 2.7 0.02 729454 32 36 0.2 0.6 0.1 3.2 0.02 729476 33 32 0.2 0.5 0.1 2.2 0.04 729494 33 40 0.2 0.7 0.2 2.5 0.02 729495 32 26 0.1 0.5 0.04 1.4 0.01 729513 33 30 0.2 0.5 0.1 2.8 0.01

Study 2 Treatment

Groups of 6- to 7-week-old male CD-1 mice (obtained from Charles River) were injected subcutaneously once a week for four weeks (for a total of 5 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized 48 hours following the final administration.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the Table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 37 Plasma chemistry markers in male CD-1 mice Compound BUN Albumin AST ALT TBIL No. (mg/dL) (g/dL) (IU/L) (IU/L) (mg/dL) PBS 19 2.6 91 132 0.3 785478 19 2.6 175 228 0.2 785502 23 2.5 479 639 0.5 785525 19 2.4 197 265 0.2 785532 15 2.2 471 591 0.3 785537 17 2.6 420 335 0.3 785539 17 2.4 143 145 0.2 785674 18 2.8 118 101 0.2 785675 19 2.7 85 62 0.2 785677 18 2.9 311 526 0.2 785920 20 3.0 875 1356 0.3 785926 24 3.3 197 232 0.2 785940 19 2.4 1201 754 0.2 786524 18 2.8 175 208 0.2 786538 18 2.9 569 1514 0.2

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 28, and the average body weight for each group is presented in the Table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the Table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 38 Body and organ weights (in grams) Compound Body Weight (g) Kidney Spleen Liver No. Day 1 Day 28 (g) (g) (g) PBS 29 38 0.6 0.1 1.9 785478 30 39 0.7 0.2 2.3 785502 29 35 0.6 0.2 1.6 785525 29 37 0.6 0.2 2.2 785532 28 33 0.6 0.4 2.7 785537 30 36 0.6 0.2 2.0 785539 30 41 0.6 0.2 2.4 785674 30 40 0.8 0.2 2.3 785675 30 39 0.7 0.2 2.5 785677 28 37 0.6 0.3 2.2 785920 29 39 0.7 0.4 3.4 785926 29 36 0.6 0.2 1.8 785940 29 30 0.6 0.1 1.8 786524 30 39 0.6 0.2 2.4 786538 30 38 0.6 0.2 3.3

Study 3 Treatment

Groups of 6- to 7-week-old male CD-1 mice (obtained from Charles River) were injected subcutaneously once a week for six weeks (for a total of 7 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized 48 hours following the final administration.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the Table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 39 Plasma chemistry markers in male CD-1 mice Compound BUN Albumin AST ALT TBIL No. (mg/dL) (g/dL) (IU/L) (IU/L) (mg/dL) PBS 25 2.5 69 60 0.2 729049 22 2.7 214 322 0.2 785478 20 2.5 166 237 0.1 785525 21 2.6 172 134 0.2 785539 18 2.6 96 64 0.2 785674 22 2.4 129 83 0.1 785675 23 2.4 98 100 0.1 785764 19 2.5 89 49 0.2 786503 20 2.4 74 47 0.1 786524 20 2.6 136 145 0.1 786548 22 2.3 132 125 0.1 786597 21 2.4 127 69 0.2

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 43, and the average body weight for each group is presented in the Table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the Table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 40 Body and organ weights (in grams) Compound Body Weight (g) Kidney Spleen Liver No. Day 1 Day 43 (g) (g) (g) PBS 28 41 0.7 0.1 2.1 729049 30 39 0.7 0.2 2.2 785478 29 39 0.7 0.2 2.4 785525 28 39 0.7 0.3 2.2 785539 28 45 0.7 0.2 2.6 785674 28 37 0.6 0.3 2.1 785675 29 41 0.7 0.2 2.7 785764 28 43 0.7 0.3 2.5 786503 29 41 0.7 0.2 2.4 786524 29 41 0.6 0.2 2.5 786548 27 41 0.6 0.2 2.4 786597 30 41 0.6 0.2 2.5

Study 4

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of 6-week-old male CD-1 mice (obtained from Charles River) were injected subcutaneously once a week for four weeks (for a total of 5 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized 48 hours following the final administration.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the Table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 41 Plasma chemistry markers in male CD-1 mice Compound BUN Albumin AST ALT TBIL No. (mg/dL) (g/dL) (IU/L) (IU/L) (mg/dL) PBS 23 2.7 80 59 0.2 728466 25 3.0 463 868 0.3 729049 24 2.6 246 253 0.2 729205 22 2.4 649 1130 0.6 729433 23 2.4 660 579 0.5 785485 25 2.6 559 701 0.3 785666 21 2.5 273 321 0.3 785764 21 2.6 78 46 0.2 785791 30 3.1 754 937 0.3 785938 24 2.7 402 348 0.4 786501 23 3.2 733 1258 0.4 786503 21 2.7 86 44 0.3 786548 22 2.6 135 142 0.2 786578 19 1.5 664 439 0.4 786597 20 2.4 136 70 0.2

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 43, and the average body weight for each group is presented in the Table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the Table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 42 Body and organ weights (in grams) Compound Body Weight (g) Kidney Spleen Liver No. Day 1 Day 43 (g) (g) (g) PBS 26 33 0.6 0.1 1.9 728466 27 33 0.4 0.2 2.4 729049 26 35 0.6 0.2 2.2 729205 24 33 0.5 0.3 3.0 729433 25 29 0.4 0.1 1.9 785485 25 28 0.4 0.2 1.4 785666 26 33 0.4 0.2 2.2 785764 25 38 0.7 0.2 2.3 785791 27 33 0.6 0.1 1.9 785938 28 31 0.4 0.3 1.6 786501 27 38 0.6 0.5 3.7 786503 26 35 0.6 0.2 2.1 786548 26 38 0.6 0.1 2.2 786578 27 37 0.6 0.2 1.7 786597 28 40 0.6 0.3 2.5

Study 5

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of 6- to 7-week-old male CD-1 mice (obtained from Charles River) were injected subcutaneously once a week for six weeks (for a total of 7 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized 48 hours following the final administration.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the Table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 43 Plasma chemistry markers in male CD-1 mice Compound BUN Albumin AST ALT TBIL No. (mg/dL) (g/dL) (IU/L) (IU/L) (mg/dL) PBS 29 3.0 57 42 0.2 665892 27 3.1 275 265 0.2 665893 25 3.2 1718 2229 2.9 728958 26 2.6 88 57 0.1 728969 27 3.4 149 142 0.2 728970 33 3.5 1142 631 0.4 729018 23 2.9 187 101 0.2 729050 26 3.1 141 119 0.2 729494 26 2.9 178 53 0.2

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 43, and the average body weight for each group is presented in the Table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the Table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 44 Body and organ weights (in grams) Body Weight (g) Compound No. Day 1 Day 43 Kidney (g) Spleen (g) Liver (g) PBS 29 37 0.6 0.1 1.8 665892 31 36 0.6 0.2 2.3 665893 30 35 0.6 0.2 2.4 728958 31 38 0.7 0.2 2.0 728969 30 37 0.6 0.2 2.3 728970 29 37 0.5 0.2 2.7 729018 31 41 0.8 0.3 2.4 729050 29 35 0.6 0.2 2.1 729494 29 37 0.6 0.2 2.2

Example 5: Tolerability of Modified Oligonucleotides Targeting Human IRF5 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety and efficacy evaluations. The rats were treated with Ionis modified oligonucleotides from the studies described in the Examples above and evaluated for changes in the levels of various plasma chemistry markers.

Study 1 Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow. Groups of 4 Sprague-Dawley rats each were weekly injected subcutaneously with 50 mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Forty-eight hours after the last dose, rats were euthanized and organs, urine and plasma were harvested for further analysis.

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. Plasma levels of total bilirubin (TBIL), creatinine, albumin, and Blood Urea Nitrogen (BUN) were also measured using the same clinical chemistry analyzer and the results are also presented in the Table below. Ionis modified oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 45 Plasma chemistry markers in Sprague-Dawley rats Compound ALT AST BUN Albumin Creatinine TBIL No. (IU/L) (IU/L) (mg/dL) (g/dL) (mg/dL) (mg/dL) PBS 57 83 16 4.9 0.4 0.2 665892 216 319 25 4.6 0.5 0.2 665893 365 472 31 4.0 0.6 0.3 728958 90 118 26 3.3 0.5 0.1 728969 154 175 24 3.4 0.5 0.2 728970 309 274 34 3.1 0.6 0.2 729018 70 98 23 3.3 0.5 0.1 729050 118 115 86 1.6 1.1 0.1 729494 60 97 43 1.6 0.5 0.1

Hematology Assays

Blood obtained from mouse groups at week 6 were sent to IDEXX BioResearch for measurement of blood cell counts. Counts taken include red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin (HGB), hematocrit (HCT), and individual white blood cell counts, such as that of monocytes (MON), neutrophils (NEU), lymphocytes (LYM), and platelets (PLT). The results are presented in the tables below. Ionis oligonucleotides that caused changes in the blood cell count outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 46 Blood Cell Count in Sprague-Dawley Rats Compound No. WBC RBC HGB HCT PBS 15 9 17 54 665892 11 9 16 51 665893 13 9 17 54 728958 18 8 14 45 728969 10 8 15 49 728970 14 8 15 49 729018  8 8 15 48 729050 16 8 13 44 729494 17 4  7 24

TABLE 47 Blood Cell Count in Sprague-Dawley Rats Compound No. NEU LYM MON PLT PBS 14 81 3.6 720 665892 15 80 4.6 620 665893 13 80 5.9 647 728958 14 82 4.1 944 728969 12 83 4.8 857 728970 12 79 8.6 837 729018 10 85 4.4 801 729050 13 75 10.1 324 729494 13 77 9.5 777

Kidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function, urinary levels of total protein and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The ratios of total protein to creatinine (P/C ratio) are presented in the Table below. Ionis oligonucleotides that caused changes in the levels of the ratio outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 48 Total protein to creatinine ratio in Sprague-Dawley rats Compound P/C No. Ratio PBS 0.7 665892 5.6 665893 5.9 728958 5.3 728969 4.1 728970 6.0 729018 4.3 729050 8.2 729494 17.2

Organ Weights

Liver, heart, spleen and kidney weights were measured at the end of the study and are presented in the Table below. Ionis oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 49 Organ weights (g) Compound Liver Kidney Spleen No. (g) (g) (g) PBS 17 3.7 0.8 665892 16 3.1 1.4 665893 14 3.1 1.0 728958 17 3.2 1.6 728969 15 3.8 1.5 728970 12 3.3 1.5 729018 15 3.1 1.7 729050 13 3.8 1.4 729494 15 4.1 2.0

Study 2 Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow. Groups of 4 Sprague-Dawley rats each were weekly injected subcutaneously with 50 mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Forty-eight hours after the last dose, the rats were euthanized; and organs, urine and plasma were harvested for further analysis.

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. Plasma levels of total bilirubin (TBIL), albumin, and blood urea nitrogen (BUN) were also measured using the same clinical chemistry analyzer and the results are also presented in the Table below. Ionis modified oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 50 Plasma chemistry markers in Sprague-Dawley rats Compound ALT AST BUN Albumin TBIL No. (IU/L) (IU/L) (mg/dL) (g/dL) (mg/dL) PBS 41 73 18 3.4 0.2 729049 70 121 154 1.4 0.1 785478 68 112 41 1.7 0.1 785525 78 118 20 3.3 0.1 785539 60 128 55 2.4 0.1 785674 64 131 22 3.2 0.1 785675 123 139 18 3.4 0.2 785764 65 95 60 1.7 0.2 786503 33 72 17 2.9 0.1 786524 64 105 21 3.1 0.2 786548 34 67 20 3.2 0.1 786597 40 66 19 2.8 0.1

Hematology Assays

Blood obtained from mouse groups at week 6 were sent to IDEXX BioResearch for measurement of blood cell counts. Counts taken include red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin (HGB), hematocrit (HCT), and individual white blood cell counts, such as that of monocytes (MON), neutrophils (NEU), lymphocytes (LYM), and platelets (PLT). The results are presented in the tables below. Ionis oligonucleotides that caused changes in the blood cell count outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 51 Blood cell count in Sprague-Dawley Rats Compound No. WBC RBC HGB HCT PBS 14 8 16 50 729049 30 5 9 27 785478 45 7 12 37 785525 18 8 14 44 785539 32 4 8 25 785674 34 8 14 43 785675 16 9 15 47 785764 22 6 10 33 786503 20 7 14 39 786524 16 8 14 44 786548 18 8 14 43 786597 28 4 7 24

TABLE 52 Blood cell count in Sprague-Dawley Rats Compound No. NEU LYM MON PLT PBS 10 84 5.5 904 729049 47 45 3.8 1418 785478 11 89 1.0 383 785525 13 77 8.6 881 785539 34 57 9.0 734 785674 12 79 7.0 731 785675 9 81 9.2 783 785764 17 76 6.8 1231 786503 10 81 7.5 650 786524 6 87 6.6 731 786548 4 87 6.6 653 786597 15 77 6.9 965

Kidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function, urinary levels of total protein and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The ratios of total protein to creatinine (P/C ratio) are presented in the Table below. Ionis oligonucleotides that caused changes in the levels of the ratio outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 53 Total protein to creatinine ratio in Sprague-Dawley rats Compound No. P/C Ratio PBS 0.8 729049 11.1 785478 15.0 785525 7.4 785539 51.1 785674 4.4 785675 2.1 785764 20.8 786503 2.5 786524 1.7 786548 2.5 786597 14.4

Organ Weights

Liver, heart, spleen and kidney weights were measured at the end of the study, and are presented in the Table below. Ionis oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 54 Organ weights (g) Compound No. Liver Kidney Spleen PBS 19 3.3 1.0 729049 19 3.5 1.1 785478 19 4.2 2.3 785525 18 3.4 1.5 785539 18 4.3 2.3 785674 17 2.7 1.6 785675 13 2.8 1.4 785764 18 4.5 2.7 786503 16 2.8 1.8 786524 14 3.2 1.8 786548 13 2.6 1.4 786597 16 3.6 2.4

Example 6: Effect of Modified Oligonucleotides on Human IRF5 Expression in a KARPAS-229 Xenograft Model in NOD Scid Mice

Male, 14-15 week old NOD Scid mice (Jackson Laboratory) were inoculated with human non-Hodgkin's Large Cell Lymphoma KARPAS-229 cells and treated with modified oligonucleotides described in the tables above or with PBS. Effects of the modified oligonucleotides on IRF5 RNA expression in the tumors and tolerability in the mice were evaluated.

Treatment

The mice were inoculated with 2 million of KARPAS-229 cells in 1:1 matrigel+KARPAS-299 suspension subcutaneously in the flank for tumor development. Modified oligonucleotide treatment started when the mean tumor size reached approximately 100 mm³. The mice were subcutaneously injected with modified oligonucleotide at a concentration of 250 mg/kg/week for two weeks, for a total of eight doses. An additional control group was similarly treated with PBS for 8 doses. On day 12 after start of treatment, the mice were sacrificed, and IRF5 levels in tumor were measured.

RNA Analysis

Primer probe set HTS4167 was used to measure human IRF5 RNA levels. Results are presented as percent change of RNA, relative to PBS control, normalized to both human GAPDH and human beta-actin or ACTB. As presented in the Table below, treatment with Ionis modified oligonucleotides resulted in significant reduction of IRF5 RNA in comparison to the PBS control. ‘0’ indicates that the oligonucleotides did not inhibit RNA expression.

TABLE 55 Modified oligonucleotide mediated inhibition of human IRF5 RNA expression in KARPAS-229 model % Inhibition Normalized Normalized Compound No. to GAPDH to ACTB PBS 0 0 728969 14 18 729018 34 47 729049 43 54 785478 34 33 785525 32 43 785674 0 26 785675 0 13 785764 0 7 786503 0 29 786524 31 43 786597 45 55

Plasma Chemistries

In addition, plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.) and the results are presented in the Table below expressed in IU/L. Plasma levels of bilirubin, albumin, and BUN were also measured using the same clinical chemistry analyzer and the results are also presented in the Table below. N/A refers to groups where data is not available, usually due to death of animal.

TABLE 56 Plasma chemistry markers in xenograft model Compound ALT AST BUN Albumin Bilirubin No. (U/L) (U/L) (mg/dL) (g/dL) (mg/dL) PBS 28 80 24 2. 0.2 728969 81 114 28 2.7 0.2 729018 317 257 22 2.5 0.2 729049 3640 2555 22 2.7 1.2 785478 4243 2610 20 2.8 1.1 785525 3989 3936 21 2.7 5.2 785674 1289 939 20 2.6 0.2 785675 411 368 18 2.5 0.1 785764 462 736 11 3.1 10.5 786503 630 717 24 2.5 0.2 786524 5094 3564 32 2.5 8.9 786597 2705 2479 24 2.4 10.7

Example 7: Effect of Antisense Inhibition of Human IRF5 in Transgenic Mouse Model

A transgenic mouse model was developed in-house using the Fosmid ABC10-44445800E12 (NCBI Clone DB ID:6338898). The clone was digested at SpeI and FspI restriction sites to produce a region containing the human IRF5 gene with 12,002 bp upstream and 5159 bp downstream of the IRF5 gene included. The gene fragment was introduced into fertilized eggs from C57BL/6 mice by pronuclear injection to produce four founder lines. Line C57BL/6-Tg(IRF5)F20.11 was used in the experiments described herein. Human IRF5 RNA expression is found in the lung, spleen, kidney, and peritoneal exudate cells (PEC) in this model. The efficacy of Ionis oligonucleotides was evaluated in this model.

Treatment

Transgenic mice were maintained on a 12-hour light/dark cycle and were fed ad libitum normal Purina mouse chow. Animals were acclimated for at least 7 days in the research facility before initiation of the experiment. Modified oligonucleotides were prepared in PBS and sterilized by filtering through a 0.2 micron filter.

The transgenic mice were divided into groups of 4 mice each for modified oligonucleotide treatment. Groups received subcutaneous injections of Ionis oligonucleotide at a dose of either 35 mg/kg once a week or 70 mg/kg once a week for three weeks (4 treatments). One group of four mice received subcutaneous injections of PBS once a week for three weeks (4 treatments). The PBS-injected group served as the control group to which oligonucleotide-treated groups were compared.

RNA Analysis

On day 23, RNA was extracted from PECs, lung and spleen for real-time RTPCR analysis of IRF5 RNA expression. Primer probe set HTS4167 was used to measure human IRF5 RNA levels. Results are presented as percent change of RNA, relative to PBS control, normalized to mouse GAPDH.

As presented in the Tables below, treatment with Ionis modified oligonucleotides resulted in significant reduction of IRF5 RNA in comparison to the PBS control. ‘0’ indicates that the oligonucleotides did not inhibit RNA expression.

TABLE 57 Modified oligonucleotide mediated inhibition (%) of human IRF5 in transgenic model (data normalized to mouse GAPDH) Dose Compound (mg/kg) No. PEC Lung Spleen PBS 0 0 0 35 728958 75 20 44 729018 53 27 30 785525 2 20 54 785674 30 7 27 785675 57 12 36 786503 53 29 55 786524 64 27 9 786548 35 2 10 70 728958 23 0 23 729018 72 19 58 785525 45 32 49 785674 76 12 49 785675 47 37 63 786503 61 23 47 786524 81 30 0 786548 75 14 52

Example 8: Effect of Modified Oligonucleotides Targeting Human IRF5 in Cynomolgus Monkeys

Cynomolgus monkeys were treated with Ionis modified oligonucleotides selected from studies described in the Examples above. Modified oligonucleotide tolerability was evaluated.

Treatment

Prior to the study, the monkeys were kept in quarantine during which the animals were observed daily for general health. The monkeys were 2-4 years old and weighed 2-4 kg. Nine groups of 4 randomly assigned male cynomolgus monkeys each were injected subcutaneously with Ionis oligonucleotide or saline in a clock-wise rotation between four different sites on the back. Following loading doses on days 1, 4 and 7, the monkeys were dosed once per week (on days 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 and 84) with 35 mg/kg of Ionis oligonucleotide. A control group of 4 cynomolgus monkeys was injected with 0.9% saline in a similar manner and served as the control group.

During the study period, the monkeys were observed twice daily for signs of illness or distress. Any animal experiencing more than momentary or slight pain or distress due to the treatment, injury or illness was treated by the veterinary staff with approved analgesics or agents to relieve the pain after consultation with the Study Director. Any animal in poor health or in a possible moribund condition was identified for further monitoring and possible euthanasia. Scheduled euthanasia of the animals was conducted on day 86 approximately 48 hours after the last dose by exsanguination while under deep anesthesia. The protocols described in the Example were approved by the Institutional Animal Care and Use Committee (IACUC).

Body and Organ Weight Measurements

To evaluate the effect of Ionis oligonucleotides on the overall health of the animals, body and organ weights were measured. Terminal body weight was measured prior to necropsy. Organ weights were measured as well, and all weight measurements are presented in the Table below. The results indicate that effect of treatment with modified oligonucleotides on body and organ weights was within the expected range for modified oligonucleotides. Specifically, treatment with ION 729018 was well tolerated in terms of the body and organ weights of the monkeys.

TABLE 58 Body and organ weights (g) Body Weight Compound (g) Day No. 86 Heart kidney spleen testes thymus liver Saline 2828 12 14 2 2 3 59 728958 2791 10 17 3 1 3 72 729018 2726 11 14 4 1 3 66 785525 3017 12 17 5 1 4 78 785674 2618 10 15 4 1 2 63 785675 2793 11 16 3 2 3 63 786503 2926 10 17 4 1 3 73 786524 2917 11 16 5 1 4 67 786548 2668  9 16 4 1 3 66

Kidney and Liver Function

To evaluate the effect of Ionis oligonucleotides on hepatic and kidney function, blood samples were collected from all the study groups on day 86. The monkeys were fasted overnight prior to blood collection. Blood was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 minutes and then centrifuged at 3000 rpm for 10 minutes to obtain serum. Levels of various liver function markers were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). Plasma levels of blood urea nitrogen (BUN), creatinine (CREA), total protein (TP), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured and the results are presented in the Table below. The results indicate that modified oligonucleotides had no effect on liver or kidney function outside the expected range for modified oligonucleotides. Specifically, treatment with ION 729018 was well tolerated in terms of the liver and kidney function in monkeys.

TABLE 59 Liver and kidney function markers in cynomolgus monkey plasma Compound BUN CREA TP ALB ALT AST TBIL No. (mg/dL) (mg/dL) (g/dL) (g/dL) (IU/L) (IU/L) (mg/dL) Saline 24 0.8 7.1 4.2 44 75 0.3 728958 26 0.8 7.0 4.2 55 99 0.2 729018 23 0.9 7.0 4.0 73 95 0.3 785525 24 1.0 7.0 4.0 44 102  0.2 785674 26 0.9 7.1 3.8 53 110  0.2 785675 25 0.8 6.8 4.0 57 96 0.3 786503 28 0.9 6.7 3.9 58 108  0.2 786524 27 0.9 7.6 3.7 58 93 0.2 786548 27 0.9 7.0 4.0 58 102  0.3

Pro-Inflammatory Proteins Analysis

To evaluate any inflammatory effect of Ionis oligonucleotides in cynomolgus monkeys, blood samples were taken for analysis. The monkeys were fasted overnight prior to blood collection. On day 84 (pre-dose and 24 hours post-dose), approximately 0.8 mL of blood was collected from each animal and put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min at room temperature to obtain serum. Complement C3 were measured using a Toshiba 120 FR NEO chemistry analyzer (Toshiba Co., Japan). The results indicate that treatment with ION 729018 did not cause any inflammation in monkeys. Another marker of inflammation, C-Reactive Protein (CRP) was tested on day 86.

TABLE 60 Pro-inflammatory protein analysis in cynomolgus monkeys Complement C3 (mg/dL) Compound Day 84 Day 84 CRP (mg/L) No. (pre-dose) (24 hr post-dose) day 86 Saline 106 104 0.1 728958 96 91 0.1 729018 93 84 0.1 785525 90 88 0.2 785674 79 71 0.1 785675 82 83 0.1 786503 93 101 0.1 786524 86 78 0.6 786548 87 92 1.2

Hematology

To evaluate any effect of Ionis oligonucleotides in cynomolgus monkeys on hematologic parameters, blood samples of approximately 0.5 mL of blood was collected from each of the available study animals on day 86. The samples were collected in tubes containing K₂-EDTA. Samples were analyzed for red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit (HCT), platelet count (PLT), white blood cells (WBC) count, individual white blood cell counts, such as that of monocytes (MON), neutrophils (NEU), and lymphocytes (LYM) using an ADVIA2120i hematology analyzer (Siemens, USA).

The data indicate the oligonucleotides did not cause any changes in hematologic parameters outside the expected range for modified oligonucleotides at this dose. Specifically, treatment with ION 729018 was well tolerated in terms of the hematologic parameters of the monkeys.

TABLE 61 Blood cell counts in cynomolgus monkeys Compound RBC HGB HCT PLT No. (×10⁶/μL) (g/dL) (%) (10³/μL) Saline 5.6 13.0 43 312 728958 5.7 12.7 43 442 729018 6.1 13.4 44 334 785525 5.4 12.2 41 459 785674 5.6 13.1 43 405 785675 5.9 13.5 45 342 786503 5.6 12.5 43 378 786524 5.8 12.6 44 252 786548 5.9 13.3 45 390

TABLE 62 Blood cell counts in cynomolgus monkeys Compound WBC NEU LYM MON No. (×10³/μL) (%) (%) (%) Saline 11 4 7 0.3 728958 10 4 6 0.3 729018 9 4 5 0.2 785525 12 4 7 0.3 785674 16 8 7 0.4 785675 9 1 7 0.3 786503 16 4 11 0.3 786524 9 4 4 0.3 786548 10 3 6 0.2

Coagulation

To evaluate effect of Ionis modified oligonucleotides on coagulation in cynomolgus monkeys, blood samples of approximately 0.9 mL were collected from each of the available study animals on day 86. The samples were collected in tubes containing 3.2% sodium citrate. Coagulation parameters tested include Activated partial thromboplastin time (APTT), prothrombin time (PT) and Fibrinogen (FIB).

The data indicate the modified oligonucleotides did not cause any changes in coagulation parameters outside the expected range for modified oligonucleotides at this dose. Specifically, treatment with ION 729018 was well tolerated in terms of the coagulation parameters of the monkeys.

TABLE 63 Coagulation Parameters in cynomolgus monkeys Compound FIB APTT No. PT (sec) (mg/dL) (sec) Saline 10 195 18 728958 10 249 19 729018 10 219 18 785525 10 208 20 785674 9 238 19 785675 9 216 19 786503 10 226 18 786524 10 235 18 786548 10 302 16

Pharmacokinetic Analysis

Accumulation of modified oligonucleotides in the liver and kidney were measured in tissues collected at necropsy. 729018 showed tissue accumulation profiles in the kidney and liver that were typical for this class of compound.

TABLE 64 Mean tissue concentration on Day 86 following 12-weeks subcutaneous administration Mean Compound Concentration Organ No. (μg/g) Kidney 728958 2078 Cortex 729018 1472 785525 1702 785674 2169 785675 1444 786503 1180 786524 1679 786548 1513 Liver 728958 657 729018 763 785525 732 785674 773 785675 753 786503 496 786524 409 786548 392

Example 9: Measurement of Viscosity of Modified Oligonucleotides Targeting Human IRF5

The viscosity of select modified oligonucleotides from the studies described above was measured with the aim of screening out modified oligonucleotides which have a viscosity of more than 40 centipoise (cP). Modified oligonucleotides having a viscosity greater than 40 cP would have less than optimal viscosity.

Oligonucleotides (32-38 mg) were weighed into a glass vial; approximately 100 μL of water was added, and the modified oligonucleotide was dissolved into solution by heating the vial to 55° C. Part (75 μL) of the pre-heated sample was pipetted to a micro-viscometer (PAC Cambridge Viscosity Viscometer). The temperature of the micro-viscometer was set to 25° C. and the viscosity of the sample was measured. The entire 75 uL of sample was them combined with the remaining portion of the sample was diluted appropriately for UV reading at 260 nM (Cary UV instrument). The data below indicates that all the modified oligonucleotides solutions are optimal in their viscosity under the criterion stated above.

TABLE 65 Viscosity of modified oligonucleotides Concentration Concentration Compound by weight by UV Viscocity No. (mg/mL) (mg/mL) (cP) 728958 300 201 17 729018 350 262 24 785524 350 277 14 785674 350 280 16 786503 300 218 40 786548 270 214 17 785675 250 209 6 786524 250 208 36

Example 10: Confirmation of Dose-Dependent Inhibition of Human IRF5 Gapmers

Modified oligonucleotides described in the studies above exhibiting significant in vitro inhibition of IRF5 mRNA were selected and tested at various doses in human A-431 cells and SH-SY5Y cells.

Study 1

Cultured A-431 cells at a density of 11,000 cells per well were treated using free uptake with modified oligonucleotides diluted to different concentrations as specified in the Tables below. After a treatment period of approximately 48 hours, IRF5 mRNA levels were measured using the Human IRF5 primer-probe set RTS37490 ((forward sequence CCACCTCAGCCCTACAAGA, designated herein as SEQ ID NO: 17; reverse sequence TCAGGCTTGGCAACATCC; designated herein as SEQ ID NO: 18; probe sequence CCTGCTCCCACAGACTCCCAG, designated herein as SEQ ID NO: 19). IRF5 mRNA levels were normalized to human GAPDH measured by primer-probe set RTS104. Results are presented in the tables below as percent inhibition of IRF5, relative to untreated control cells.

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide is also presented. IC₅₀ was calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 66 Multi-dose assay of modified oligonucleotides in A-431 cells % Inhibition Compound 23.44 93.75 375.00 1500.00 6000.00 IC₅₀ No. nM nM nM nM nM (μM) 728958  0 16 36 57 71 1.07 729018 31 72 93 98 99 0.05 785525 32 68 88 95 97 0.05 785675  7 27 57 80 90 0.28 786503 29 70 93 98 99 0.05

Study 2

Cultured SH-SY5Y cells at a density of 45,000 cells per well were treated using electroporation with modified oligonucleotides diluted to different concentrations as specified in the Tables below. After a treatment period of approximately 24 hours, IRF5 mRNA levels were measured using the Human IRF5 primer-probe set RTS37490. IRF5 mRNA levels were normalized to human GAPDH measured by primer-probe set RTS104. Results are presented in the tables below as percent inhibition of IRF5, relative to untreated control cells.

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide is also presented. IC₅₀ was calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 67 Multi-dose assay of modified oligonucleotides in SH-SY5Y cells % Inhibition Compound 23.44 93.75 375.00 1500.00 6000.00 IC₅₀ No. nM nM nM nM nM (μM) 728958  0  0 23 47 64 1.07 729018  8 19 46 66 80 0.05 785525  8 15 36 68 80 0.05 785675  0  0 17 42 65 0.28 786503 22 15 32 64 80 0.05

Example 11: Evaluation of Proinflammatory Effects in hPBMC Assay

Human IRF5 modified oligonucleotides were tested for potential immunostimulatory properties in an in vitro human peripheral blood mononuclear cell (PBMC) activation assay. Human PBMCs were isolated from fresh whole blood donated by healthy donors (with informed consent at US HealthWorks clinic, Carlsbad). The blood was collected into 8 mL Vacutainer CPT tubes that contained sodium citrate anticoagulant and Ficoll density media with polyester gel barrier separating those liquids. Following centrifugation of CPT tubes at 1215 rpm in Beckman Allegra 6R centrifuge, red blood cells and granulocytes were separated from plasma and PBMCs by polyester gel barrier. PBMCs accumulated at the interface between Ficoll and plasma, just above the polymer gel layer. Purified PBMCs were washed with PBS (Ca⁺⁺, Mg⁺⁺ free), and resuspended in RPMI culture medium (RPMI containing 10% FBS and penicillin and streptomycin). Only PBMC preps with viability >80% were used for the assay. The average viability of the PBMC used in these assays was 86.6%.

For cultures, PBMC were plated at 5×10⁵ cells/well in sterile, 96-round bottomed polypropylene plates. Cells were treated with increasing concentrations of modified oligonucleotides targeting human IRF5 (as indicated in tables below) and incubated for 24 hours at 37° C. and 5% CO₂. ION No. 353512 (3-14-3 MOE gapmer, TCCCATTTCAGGAGACCTGG, designated herein as SEQ ID NO: 35) is an internal standard known to be a high responder for IL-6 release in the assay. ION No. 104838 (5-10-5 MOE gapmer, GCTGATTAGAGAGAGGTCCC, designated herein as SEQ ID NO: 36) is an internal standard known to be a non-responder in the assay (a negative control). After a 24-hour incubation, plates were centrifuged at 330 g for 5 min; supernatants were collected for MSD human Proinflammatory Panel 1_V-plex (custom 4-plex) cytokine assay. Multiplex MSD cytokine assay was conducted following the manufacturer's instructions to measure levels of IL-6, IL-10, and TNF-α in the supernatant. Electrochemiluminescence was measured using Sector Imager 2400 (Meso Scale Discovery) and data analyzed using MSD Discovery Workbench® software.

Levels of IL-6, IL-10 and TNF-α measured are presented in the Tables below. Many of the oligonucleotides tested were deemed tolerable. ION No. 729018 consistently elicited similar or less cytokine production than the negative control oligonucleotide.

TABLE 68 IL-6 levels following treatment of human PBMCs with modified oligonucleotides Concentration Compound No. (uM) 728958 729018 785525 785674 785675 786503 786524 786548 353512 104838  0 172 162 144 148 219 193 198 194 213 205  0.0128 212 180 211 201 245 159 189 247 198 211  0.064 228 201 211 211 217 207 204 184 206 307  0.32 264 183 301 298 292 246 212 297 381 339  1.6 216 208 355 391 376 271 208 273 332 258  8.0 254 243 370 353 436 341 242 290 472 297  40.0 326 276 456 417 491 342 217 282 470 332 200.0 2709  286 745 502 738 446 286 452 632 524

TABLE 69 IL-10 levels following treatment of human PBMCs with modified oligonucleotides Concentration Compound No. (uM) 728958 729018 785525 785674 785675 786503 786524 786548 353512 104838 0 7 12 6 8 10 9 9 9 8 7 0.0128 7 8 10 8 10 7 8 8 13 6 0.064 27 36 9 12 13 10 8 9 43 12 0.32 13 15 20 28 37 25 9 14 66 24 1.6 10 24 40 47 55 31 13 18 52 24 8.0 14 26 29 43 60 34 18 20 28 21 40.0 9 17 11 20 27 15 21 13 11 11 200.0 13 5 7 9 9 8 15 5 8 6

TABLE 70 TNF-α levels following treatment of human PBMCs with modified oligonucleotides Concentration Compound No. (uM) 728958 729018 785525 785674 785675 786503 786524 786548 353512 104838 0 11 10  9  9 11 10 10 11 12 12 0.0128 9 10 11 12 12 14 10 11 11 11 0.064 15 22 10 10 10 10 9 10 14 12 0.32 16 11 13 12 13 11 8 11 17 14 1.6 11 13 19 16 17 15 10 13 22 15 8.0 13 14 25 20 25 20 12 15 35 20 40.0 22 20 40 32 35 26 16 19 41 28 200.0 92 28 115  50 63 36 24 29 89 55

Example 12: Dose-Dependent Inhibition of Human IRF5 in A-431 Cells by Modified Oligonucleotides

Modified oligonucleotides described in the studies above exhibiting significant in vitro inhibition of IRF5 RNA were selected and tested at various doses in Human A-431 cells.

Cultured A-431 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to different concentrations as specified in the Tables below. After a treatment period of approximately 48 hours, IRF5 mRNA levels were measured as previously described using the Human IRF5 primer-probe set RTS4524. IRF5 mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent inhibition of IRF5, relative to untreated control cells. The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide is also presented.

TABLE 71 Multi-dose assay of modified oligonucleotides in A-431 cells % Inhibition 4.57 13.72 41.152 123.457 370.37 1111.111 3333.33 10000.0 IC₅₀ Compound No. nM nM nM nM nM nM nM nM (μM) 729018 0 11 41 64 77 83 86 88 0.1 786503 0  2 26 57 71 82 88 89 0.1 786524 0 10 28 53 78 85 88 89 0.1

Example 13: Design and Dose-Dependent Inhibition of Modified Oligonucleotides Targeting Human IRF5

Modified oligonucleotides with additional chemistry modifications were designed overlapping the active sites of 729018, 786503, and 785675, which were selected based on studies above. The newly designed oligonucleotides were tested for in vitro inhibition of human IRF5 mRNA in human A-431 cells. Several different chemistry modifications were tested, which are specified in the Chemistry Notation column of the tables below, wherein the notation “d” refers to a 2′-deoxyribose sugar, the notation “s” refers to a phosphorothioate internucleoside linkage, the notation “k” refers to a cEt modified sugar, the notation “y” refers to a 2′-o-methyl ribose sugar, the notation “MOP” refers to a methoxypropyl phosphonate internucleoside linkage, and the notation “^(m)C” refers to a 5-methyl cytosine. In some instances, the thymine was replaced by uracil.

TABLE 72 List of modified oligonucleotides designed for dose-dependent inhibition study SEQ ID NO: 2 SEQ Compound Start Sequence Chemistry ID No. Site (5′ to 3′) Notation NO 785675 4366 TGTCT T_(ks)G_(ks)T_(ds) ^(m)C_(ds) 1340 AGTGT T_(ds)A_(ds)G_(ds)T_(ds) CATGG G_(ds)T_(ds) ^(m)C_(ds)AC_(s) A T_(es)GC_(s)G_(ks)A_(e) 1073764 4366 TGTCT T_(ks)G_(ks)T_(ds) ^(m)C_(ks) 1340 AGTGT T_(ds)A_(ds)G_(ds)T_(ds) CATGG G_(ds)T_(ds) ^(m)C_(ds) A A_(es)T_(es)G_(es)G_(ks) A_(k) 1073765 4366 TGTCT T_(ks)G_(ks)T_(ds) ^(m)C_(ds) 1340 AGTGT T_(ks)A_(ds)G_(ds)T_(ds) CATGG G_(ds)T_(ds) ^(m)C_(ds)A_(es) A T_(es)G_(es)G_(ks)A_(k) 1073766 4366 TGTCT T_(ks)G_(ks)T_(ds) ^(m)C_(dMOP) 1340 AGTGT T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) CATGG T_(ds) ^(m)C_(ds)A_(es)T_(es) A G_(es)G_(ks)A_(k) 1073767 4366 TGTCT T_(ks)G_(ks)T_(ds) ^(m)C_(ds) 1340 AGTGT T_(dMOP)A_(ds)G_(ds)T_(ds) CATGG G_(ds)T_(ds) ^(m)C_(ds)A_(es) A T_(es)G_(es)G_(ks)A_(k) 1073768 4366 TGTCT T_(ks)G_(ks)T_(ds)C_(ys)T_(ds) 1340 AGTGT A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) CATGG ^(m)C_(ds)A_(es)T_(es)G_(es) A G_(ks)A_(k) 1073769 4366 TGTCU T_(ks)G_(ks)T_(ds) ^(m)C_(ds) 1356 AGTGT U_(ys)A_(ds)G_(ds)T_(ds) CATGG G_(ds)T_(ds) ^(m)C_(ds)A_(es) A T_(es)G_(es)G_(ks)A_(k) 786503 11736 CTGAT ^(m)C_(ks)T_(ks)G_(ks)A_(ds) 1270 ATGAT T_(ds)A_(ds)T_(ds)G_(ds) ACCTA A_(ds)T_(ds)A_(ds) ^(m)C_(ds) A ^(m)C_(ds)T_(ks)A_(ks)A_(k) 1072783 11736 CTGAT ^(m)C_(ks)T_(ks)G_(ks)A_(ds) 1270 ATGAT T_(ks)A_(ds)T_(ds)G_(ds) ACCTA A_(ds)T_(ds)A_(ds) ^(m)C_(ds) A ^(m)C_(ds)T_(ks)A_(ks)A_(k) 1072784 11736 CTGAT ^(m)C_(ks)T_(ks)G_(ks)A_(ds) 1270 ATGAT T_(ds)A_(ks)T_(ds)G_(ds)A_(ds) ACCTA T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) A T_(ks)A_(ks)A_(k) 1072785 11736 CTGAT ^(m)C_(ks)T_(ks)G_(ks)A_(ds) 1270 ATGAT T_(dMOP)A_(ds)T_(ds)G_(ds) ACCTA A_(ds)T_(ds)A_(ds) ^(m)C_(ds) A ^(m)C_(ds)T_(ks)A_(ks)A_(k) 1072786 11736 CTGAT ^(m)C_(ks)T_(ks)G_(ks)A_(ds)T_(ds) 1270 ATGAT A_(dMOP)T_(ds)G_(ds)A_(ds) ACCTA T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) A T_(ks)A_(ks)A_(k) 1072788 11736 CTGAT ^(m)C_(ks)T_(ks)G_(ks)A_(ds)T_(ds) 1270 ATGAT A_(ys)T_(ds)G_(ds)A_(ds)T_(ds) ACCTA A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) A A_(ks)A_(k) 1072787 11736 CTGAU ^(m)C_(ks)T_(ks)G_(ks)A_(ds)U_(ys) 1355 ATGAT A_(ds)T_(ds)G_(ds)A_(ds)T_(ds) ACCTA A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) A A_(ks)A_(k) 729018 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ds) 228 TATGA T_(ds)A_(ds)T_(ds)G_(ds)A_(ds) TACCT T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) A T_(ks)A_(k) 1072777 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds) 228 TATGA A_(ks)T_(ds)A_(ds)T_(ds)G_(ds) TACCT A_(ds)T_(ds)A_(ds) ^(m)C_(ds) A ^(m)C_(ks)T_(ks)A_(k) 1072778 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ds) 228 TATGA T_(ks)A_(ds)T_(ds)G_(ds)A_(ds) TACCT T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) A T_(ks)A_(k) 1072779 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds) 228 TATGA A_(dMOP)T_(ds)A_(ds)T_(ds) TACCT G_(ds)A_(ds)T_(ds)A_(ds) ^(m) A C_(ds) ^(m)C_(ks)T_(ks)A_(k) 1072780 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds) 228 TATGA A_(ds)T_(dMOP)A_(ds)T_(ds) TACCT G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) A ^(m)C_(ks)T_(ks)A_(k) 1072781 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ys) 228 TATGA T_(ds)A_(ds)T_(ds)G_(ds)A_(ds) TACCT T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) A T_(ks)A_(k) 1072782 11737 TCTGA T_(ks) ^(m)C_(ks)T_(ks)G_(ds)A_(ds) 1354 UATGA U_(ys)A_(ds)T_(ds)G_(ds)A_(ds) TACCT T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) A T_(ks)A_(k)

Cultured A-431 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to different concentrations as specified in the Tables below. After a treatment period of approximately 72 hours, IRF5 mRNA levels were measured using the Human IRF5 primer-probe set RTS4524. IRF5 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of IRF5 relative to untreated control cells. As used herein, a value of ‘0’ indicates that treatment with the modified oligonucleotide did not inhibit IRF5 mRNA levels.

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide is also presented. IC₅₀ was calculated using a linear regression on a log/linear plot of the data in excel. Data below shows that 729018 shows significant activity against human IRF5 compared to all other modified oligonucleotides tested.

TABLE 73 Multi-dose assay of modified oligonucleotides in A-431 cells Com- % Inhibition pound 4.12 12.25 37.04 111.11 333.33 1000 No. nM nM nM nM nM nM 729018 8 27 54 78 89 92 1072777 0 7 43 65 81 85 1072778 4 8 36 54 69 74 1072779 10 14 43 66 80 87 1072780 10 6 38 56 71 77 1072781 1 8 35 57 77 81 1072782 0 12 35 58 79 83 786503 13 29 54 80 88 90 1072783 20 29 38 64 83 83 1072784 18 23 41 63 80 75 1072785 11 22 29 56 76 78 1072786 0 15 25 54 71 71 1072787 6 23 41 64 82 82 1072788 1 14 31 56 74 79 785675 0 0 24 44 59 69 785675 4 2 28 44 60 74 1073764 0 5 6 24 23 41 1073765 0 0 9 17 13 29 1073766 0 15 10 39 58 75 1073767 2 11 4 8 18 32 1073768 0 11 5 15 25 33 1073769 0 7 10 26 46 62 

What is claimed:
 1. A compound comprising a modified oligonucleotide consisting of 16 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising a 16 nucleobase portion that is at least 80% complementary to an equal length portion of any of the nucleobase sequences of SEQ ID NOs: 37-1356; and wherein the modified oligonucleotide comprises at least one modification selected from at least one modified internucleoside linkage, at least one modified sugar, and at least one modified nucleobase that is a 5-methylcytosine.
 2. The compound of claim 1, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
 3. The compound of claim 1, wherein the modified sugar is a bicyclic sugar.
 4. The compound of claim 4, wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH₂)—O-2′ (LNA), 4′-(CH₂)₂—O-2′ (ENA), and 4′-CH(CH₃)—O-2′ (cEt).
 5. The compound of claim 1, wherein the modified sugar is 2′-O-methoxyethyl.
 6. The compound of claim 1, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; and a 3′ wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
 8. The compound of claim 7, wherein each internucleoside linkage is a phosphothiorate linkage, each cytosine is a 5-methylcytosine, and each nucleoside of each wing segment comprises a cEt sugar.
 9. A composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier.
 10. A compound comprising a modified oligonucleotide consisting of 16 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising a 16 nucleobase portion that is at least 80% complementary to an equal length portion of nucleobases 4366-4381, 5141-5156, 5140-5160, 5179-5194, 5567-5642, 5644-5731, 5567-5731, 5567-5620, 11544-11559, 11542-11596, 11736-11751, 11720-11790, 11794-11809, 13697-13733, 20553-20676, 20664-20824, 20553-20824, or 25844-25912 of SEQ ID NO: 2; and wherein the modified oligonucleotide comprises at least one modification selected from at least one modified internucleoside linkage, at least one modified sugar, and at least one modified nucleobase that is a 5-methylcytosine.
 11. The compound of claim 10, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
 12. The compound of claim 10, wherein the modified sugar is a bicyclic sugar.
 13. The compound of claim 12, wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH₂)—O-2′ (LNA), 4′-(CH₂)₂—O-2′ (ENA), and 4′-CH(CH₃)—O-2′ (cEt).
 14. The compound of claim 10, wherein the modified sugar is 2′-O-methoxyethyl.
 15. The compound of claim 10, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; and a 3′ wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
 16. The compound of claim 15, wherein each internucleoside linkage is a phosphothiorate linkage, each cytosine is a 5-methylcytosine, and each nucleoside of each wing segment comprises a cEt sugar.
 17. A composition comprising the compound of claim 10, and a pharmaceutically acceptable carrier.
 18. A method of treating, preventing, or ameliorating a disease associated with IRF5 in an individual in need thereof, comprising administering to the individual the compound of claim 10, thereby treating, preventing, or ameliorating the disease.
 19. The method of claim 18, wherein the disease is an inflammatory bowel disease.
 20. The method of claim 19, wherein the inflammatory bowel disease is ulcerative colitis.
 21. The method of claim 19, wherein the inflammatory bowel disease is Crohn's disease.
 22. A method of inhibiting or reducing inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual in need thereof, comprising administering to the individual the compound of claim 10, thereby inhibiting or reducing inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in the individual. 